Dextrorphan prodrugs and processes for making and using them

ABSTRACT

The presently described technology provides compositions of one or more of oxoacids, polyethylene glycols, and/or vitamin compounds chemically conjugated to dextrorphan, (+)-17-methylmorphinan-3-ol), to form novel prodrugs and compositions of dextrorphan.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/604,755, filed Oct. 11, 2019 and claims priority to InternationalPatent Application No. PCT/US2018/027266 which was filed Apr. 12, 2018,which claims priority to U.S. provisional application No. 62/485,894,filed on Apr. 14, 2017, which is herein incorporated by reference in itsentirety. This application is also related to U.S. provisionalapplication No. 62/485,888, filed on Apr. 14, 2017; U.S. provisionalapplication No. 62/485,890, filed on Apr. 14, 2017; and U.S. provisionalapplication No. 62/485,891, filed on Apr. 14, 2017.

BACKGROUND

Opioids are highly effective as analgesics and are commonly prescribedfor the treatment of acute and chronic pain. They are also commonly usedas antitussives. The opioids, however, also produce euphoria and arehighly addictive. As a result, they are often abused with far reachingsocial and health related consequences.

Because of the inherent potential for abuse, it is desirable that anypharmaceutical composition containing an opioid agonist be made asabuse-resistant or abuse-deterrent as practical. Illicit users oftenwill attempt to circumvent the extended release properties of thesedosage forms by injecting or otherwise misusing the product in order toachieve an immediate release of the opioid agonist.

Dextrorphan ((+)-17-methylmorphinan-3-ol) is the (+)-isomer and one oftwo enantiomers of 17-methylmorphinan-3-ol. The other enantiomer islevorphanol ((−)-17-methylmorphinan-3-ol). A 1:1 mixture of bothenantiomers (dextrorphan and levorphanol) is referred to as racemorphan.

It should be appreciated by those skilled in the art that differentstereochemistry may impact the pharmacodynamics, pharmacological and/orpharmacokinetic properties, among other properties, of each isomer orracemic mixture utilized. Further, it should also be appreciated thatvarious conjugations of the isomers to various ligands may also impactthe pharmacodynamics, pharmacological and/or pharmacokinetic properties,among other properties, of each resultant conjugate, formulation, and/orend product. For example, those skilled in the art can appreciate thepharmacodynamics, pharmacological and/or pharmacokinetic propertydifferences exhibited and/or observed by different enantiomers(dextrorphan and levorphanol) as well as a mixture such as racemorphan.Moreover, those skilled in the art, also appreciate that the conjugationof those various different enantiomers may impact the various propertiesobserved for the resultant dextrorphan or levorphanol conjugate,formulation and/or end product. Furthermore, those skilled in the artcan recognize that conjugation to dextrorphan, levorphanol, or a mixturethereof, may create new enantiomers or diastereomers that may affecttheir resulting pharmacodynamic, pharmacological and/or pharmacokineticproperties.

Dextrorphan is a psychoactive drug of the morphinan class which acts asan antitussive or cough suppressant and dissociative hallucinogen. It isalso an active metabolite of dextromethorphan that forms afterO-demethylation by CYP2D6. Dextrorphan is an NMDA (N-methyl-D-aspartate)receptor antagonist. Dextrorphan also binds to the σ₁-receptor, and to alesser extent to the norepinephrine reuptake transporter (NET) and tothe serotonin reuptake transporter (SERT). Dextrorphan can act, forexample, as an anesthetic and antitussive.

The present technology utilizes covalent conjugation of dextrorphan withcertain oxoacids including amino acids, as well as with polyethyleneglycols (PEG or PEO), and/or vitamin compounds to decrease its potentialfor causing overdose or abuse by requiring the active dextrorphan to bereleased through enzymatic or metabolic breakdown of the conjugate invivo. The present technology also provides methods of deliveringdextrorphan as conjugates that release the dextrorphan following oraladministration while being resistant to abuse by circuitous routes suchas intravenous (“shooting”) injection and intranasal administration(“snorting”). The compounds and conjugates of this disclosure (akaprodrugs) may be administered alone, or combined with other activeingredients, for the treatment of conditions including, but not limitedto, cough, pseudobulbar affect (PBA), neuropathy, diabetic peripheralneuropathic pain, catalepsy, amnesia, Alzheimer's disease, depression,and post-traumatic stress disorder (PTSD).

BRIEF SUMMARY

The present technology utilizes conjugation of the dextrorphan withcertain oxoacids (including amino acids), polyethylene glycols (PEG orPEO), and/or vitamin compounds to decrease its potential for causingoverdose or abuse by requiring the active dextrorphan to be releasedthrough enzymatic or metabolic breakdown of the conjugate in vivo. Thepresent technology also provides methods of delivering dextrorphan asconjugates that release the dextrorphan following oral administrationwhile being resistant to abuse by circuitous routes such as intravenous(“shooting”) injection and intranasal administration (“snorting”).

Advantages of certain embodiments of the dextrorphan prodrugs of thepresent technology include, but are not limited to, reduced risk ofchemical or physical manipulation resulting in full dosage ofdextrorphan release, reduced patient to patient variability in plasmaconcentrations compared to free dextrorphan, improved dosage formsthrough modifications of the physical and chemical properties of theprodrugs.

In some aspects, the present technology provides an immediate releasecomposition of conjugated dextrorphan that allows delivery of thedextrorphan into the blood system of a human or animal in atherapeutically bioequivalent manner upon oral administration. In atleast one aspect, the compositions/formulations of the currenttechnology can lessen common side effects associated with unconjugateddextrorphan and similar compounds. The presently described technology,in at least one aspect, provides a slow/sustained/controlled releasecomposition of conjugated dextrorphan that allowsslow/sustained/controlled delivery of the dextrorphan into the bloodsystem of a human or animal within a therapeutic window upon, forexample, oral administration.

In one aspect, the present technology provides a composition comprisingat least one conjugate of dextrorphan, and at least one oxoacid,polyethylene glycol, vitamin compound, derivatives thereof, orcombinations thereof. In some aspects, the conjugate further comprises alinker, wherein the linker chemically bonds the at least one dextrorphanwith the at least one oxoacid, polyethylene glycol, vitamin compound, orderivatives thereof.

In another aspect, the present technology provides at least oneconjugate of dextrorphan, and at least one oxoacid, polyethylene glycol,vitamin compound, derivatives thereof, or combinations thereof. In someaspects, the conjugate further comprises a linker, wherein the linkerchemically bonds the at least one dextrorphan with the at least oneoxoacid, polyethylene glycol, vitamin compound, or derivatives thereof.

In a further aspect, the present technology provides a compositioncomprising at least one conjugate of dextrorphan, wherein the conjugatehas the following general Formula IA:

where L¹ is absent, or is

Y¹ is absent, or [A-X—Z]_(n)

where A, X, Z are independently absent or selected from —O—, —S— or—(CR¹R²)_(k)—

R¹, R² are independently selected from H, alkyl, aryl, alkylaryl,alkoxy, haloalkyl, or haloaryl

n and k are independently 1-4

G_(m) ¹ is absent or selected independently for each repeating subunitfrom H, oxoacid, polyethylene glycol having from 2 to 5 ethylene oxideunits, or a vitamin compound, and m is 1-4, except that m is 1 when G¹is a hydrogen atom;

or a pharmaceutically acceptable salt thereof.

In a further aspect, the present technology provides a compositioncomprising at least one conjugate of dextrorphan, wherein the conjugatehas the following general Formula IB:

-   -   where L² is absent, or is

-   -   Y² is absent, or [A-X—Z]_(n)    -   where A, X, Z are independently absent or selected from —O—, —S—        or —(CR¹R²)_(k)—    -   J is [M-W]_(p)    -   where M is absent, or —(CR³R⁴)_(q)—; and W is absent, or —O— or        —S—    -   R¹, R², R³, R⁴ are each independently selected from H, alkyl,        aryl, alkylaryl, alkoxy, haloalkyl, or haloaryl    -   n and k are independently 1-4    -   p and q are independently 1-4    -   G_(m) ² is absent or selected independently for each repeating        subunit from H, oxoacid, polyethylene glycol having from 2 to 5        ethylene oxide units, or a vitamin compound, and m is 1-4,        except that m is 1 when G² is a hydrogen atom;    -   or a pharmaceutically acceptable salt thereof.

In a further aspect, the present technology provides a compositioncomprising at least one conjugate of dextrorphan, wherein the conjugatehas the following general Formula IC:

-   -   where L¹ and L² are independently absent, or

-   -   Y¹ and Y² are independently either absent, or [A-X—Z]_(n)    -   where A, X, Z are independently selected for Y¹ and Y², and are        independent of each other, either absent or selected from —O—,        —S—, or —(CR¹R²)_(k)—    -   J is [M-W]_(p)    -   where M is absent, or —(CR³R⁴)_(q)—; and W is absent, or —O— or        —S—    -   R¹ and R² are each independently selected for Y¹ and Y², and        are, independent of each other, selected from H, alkyl, aryl,        alkylaryl, alkoxy, haloalkyl, or haloaryl    -   R³ and R⁴ are each independently selected from H, alkyl, aryl,        alkylaryl, alkoxy, haloalkyl, or haloaryl    -   for each Y¹ and Y², n is independently an integer of 1-4    -   for each repeating unit of [A-X—Z]_(n), when (CR¹R²)_(k) is        present, k is independently an integer of 1-4.    -   p and q are independently 1-4    -   G_(m) ¹ and G_(m) ² are independently absent, or selected        independently of each other and, when present, each repeating        subunit is independently selected from H, oxoacid, polyethylene        glycol having from 2 to 5 ethylene oxide units, or a vitamin        compound;    -   where m is selected independently for G¹ and G², and is an        integer of 1-4,    -   except that m is 1 when G¹ or G² is a hydrogen atom;    -   or a pharmaceutically acceptable salt thereof.

In another aspect, the present technology provides at least one prodrugor conjugate having the structure of general Formula 1A, 1B, or 1C.

In a further aspect, the present technology provides at least oneprodrug composition comprising at least one conjugate of dextrorphan andat least one oxoacid, polyethylene glycol, vitamin compound, derivativesthereof, or combinations thereof. In some embodiments, the prodrugcomposition may also comprise conjugate combinations, and/or one or moreactive ingredients, additives, adjuvants, or combinations thereof.

In another aspect, the present technology provides at least one prodrugcomposition comprising at least one conjugate, where dextrorphan isconjugated at the C-3 hydroxyl position, and wherein the at least oneconjugate can be, for example, 3-Val-dextrorphan;3-(N-acetyl-Val)-dextrorphan; 3-(PhePhePhe)-dextrorphan;3-(ValValPhe)-dextrorphan; 3-(AlaAlaVal)-dextrorphan;3-(GlyGlyAla)-dextrorphan; 3-hippuryl-dextrorphan;3-(N-acetyl-Tyr)-dextrorphan; 3-(N-acetyl-Ile)-dextrorphan;3-(ProProPhe)-dextrorphan; 3-(GlyGly)-dextrorphan;3-(ValGly)-dextrorphan; 3-(AlaPro)-dextrorphan; 3-cinnamoyl-dextrorphan;3-biotinyl-dextrorphan; 3-(N,O-diacetyl-Tyr)-dextrorphan;3-(N-acetyl-Val-OCH₂OC(O))-dextrorphan;3-(cinnamoyl-OCH₂OC(O))-dextrorphan; 3-(benzoyl-OCH₂OC(O)-dextrorphan;3-(butanoyl-OCH₂OC(O))-dextrorphan;3-(N,O-acetyl-Lys-OCH₂OC(O))-dextrorphan;3-(acetyl-OCH(CH₃)C(O))-dextrorphan; 3-(acetyl-OCH₂C(O))-dextrorphan;3-(acetyl-OCH(phenyl)C(O))-dextrorphan;3-(methoxy-PEG₂-CH₂C(O))-dextrorphan;3-(methoxy-(ethoxy)-CH₂C(O))-dextrorphan;3-(N-succinoyl-Val)-dextrorphan; 3-(H₂N-PEG₄-CH₂CH₂C(O))-dextrorphan;3-(N₃-PEG₄-CH₂CH₂C(O))-dextrorphan; 3-(H₂N-PEG₅-CH₂CH₂C(O))-dextrorphan,3-(propyl-SC(O))-dextrorphan, 3-(ethoxy-C(O))-dextrorphan and anionicsalts thereof, including hydrochloride/chloride salts.

In another aspect, the present technology provides at least one prodrugcomposition comprising at least one conjugate, where dextrorphan isconjugated at the N-17 position, and wherein the at least one conjugatecan be, for example, N-(acetyl-OCH₂)-dextrorphanium;N-(pivaloyl-OCH₂)-dextrorphanium; N-(Ser-Ile-CH₂)-dextrorphanium;N-(Val-CH₂)-dextrorphanium; N-(Phe-Val-CH₂)-dextrorphanium;3-(Phe-CH(Me)C(O))—N-(nicotinoyl-OCH₂)-dextrorphanium;N-(MeO-PEG₃-CH₂C(O)OCH₂)-dextrorphanium;N—(HO-PEG₄-CH₂CH₂C(O)CH₂)-dextrorphanium;N—(BzO-CH₂OC(O)OCH₂)-dextrorphanium;N-(Ala-CH₂OC(O)OCH₂)-dextrorphanium;N-(Pro-Val-CH₂OC(O)OCH₂)-dextrorphanium;N-(thiaminyl-C(O)OCH₂)-dextrorphanium;N-(cinnamoyl-OCH₂SC(O)SCH₂)-dextrorphanium; and anionic salts thereof,including hydrochloride/chloride salts.

In another aspect, the present technology provides at least one prodrugcomposition comprising at least one conjugate, where dextrorphan isconjugated at both the C-3 hydroxyl and the N-17 position, and whereinthe at least one conjugate can be, for example,3-acetyl-N-(acetyl-OCH₂)-dextrorphanium;3-(pivaloyl)-N-(pivaloyl-OCH₂)-dextrorphanium;3-(ethoxy-C(O))—N-(ethoxy-C(O)CH(CH₃))-dextrorphanium;3-(EtO-C(O))—N—(H₂N-PEG₂-CH₂CH₂C(O)OCH₂)-dextrorphanium;3-(Ac-Val)-N-(Phe-Phe-CH₂)-dextrorphanium;3-(acetylsalicyloyl-OCH₂OC(O))—N—(Ac-Val-CH₂)-dextrorphanium;3-(Phe-CH(Me)C(O))—N-(nicotinoyl-OCH₂)-dextrorphanium, and saltsthereof, including hydrochloride/chloride salts.

In yet another aspect, the present technology provides a method forchemically synthesizing any of the dextrorphan conjugates of the presenttechnology by performing the appropriate steps to conjugate dextrorphanto at least one ligand.

In a further aspect, the present technology provides a method fortreating a human or animal patient having a disease, disorder orcondition requiring or mediated by binding of an NMDA receptorantagonist to an NMDA receptor of the patient, comprising orallyadministering to the patient a pharmaceutically effective amount of atleast one dextrorphan conjugate of the present technology.

In another aspect, the present technology provides a pharmaceutical kitcomprising a specified amount of individual doses in a package, eachdose comprising a pharmaceutically effective amount of at least oneconjugate of dextrorphan.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Chemical structures of some hydroxybenzoates for use in themaking of the conjugates of the present technology.

FIG. 2. Chemical structures of some aminobenzoic acids for use in themaking of the conjugates of the present technology.

FIG. 3. Chemical structures of some heteroaryl carboxylic acids for usein the making of the conjugates of the present technology.

FIG. 4. Chemical structures of some phenylacetates for use in the makingof the conjugates of the present technology.

FIG. 5. Chemical structures of some benzylacetates for use in the makingof the conjugates of the present technology.

FIG. 6. Chemical structures of some cinnamates for use in the making ofthe conjugates of the present technology.

FIG. 7. Chemical structures of some dicarboxylic acids for use in themaking of the conjugates of the present technology.

FIG. 8. Chemical structures of some tricarboxylic acids for use in themaking of the conjugates of the present technology.

FIG. 9. Chemical structures of some standard amino acids for use in themaking of the conjugates of the present technology.

FIG. 10. Chemical structures of some non-standard amino acids for use inthe making of the conjugates of the present technology.

FIG. 11. Chemical structures of some synthetic amino acids for use inthe making of the conjugates of the present technology.

FIG. 12A. Chemical structures of some water soluble vitamins for use inthe making of the conjugates of the present technology.

FIG. 12B. Chemical structures of some fat soluble vitamins for use inthe making of the conjugates of the present technology.

FIG. 13. Oral PK curves comparing 3-(N-acetyl-Val)-dextrorphan conjugateand 3-(N-acetyl-Val-OCH₂OC(O))-dextrorphan conjugate with unconjugateddextrorphan in rats.

FIG. 14. Oral PK curves comparing 3-Val-dextrorphan conjugate withunconjugated dextrorphan in rats.

FIG. 15. Oral PK curves comparing N-(acetyl-OCH₂)-dextrorphaniumconjugate with unconjugated dextrorphan in rats.

FIG. 16. Oral PK curves comparing3-acetyl-N-(acetyl-OCH₂)-dextrorphanium conjugate with unconjugateddextrorphan in rats.

FIG. 17. Intranasal PK curves comparing 3-(N-acetyl-Val)-dextrorphanconjugate with unconjugated dextrorphan in rats.

DETAILED DESCRIPTION

The present technology provides compounds of, or compositions comprisingone or more oxoacids, polyethylene glycols and/or vitamin compounds(“ligands”) that are chemically conjugated to dextrorphan((+)-17-methylmorphinan-3-ol) to form novel prodrugs and conjugates ofdextrorphan. In some embodiments, the chemical bond between the ligandsand dextrorphan can be established by reacting the functional group ofthe ligand, either directly or through a linking group, with one of thefollowing functional groups of dextrorphan:

(a)C-3 hydroxyl of dextrorphan,

(b) N-17 tertiary amine of dextrorphan,

(c) or both C-3 hydroxyl and N-17 tertiary amine of dextrorphan.

In some embodiments, the chemical bond between the ligands anddextrorphan can be established by reacting the C-3 hydroxyl ofdextrorphan with the activated carboxylic acid function of an oxoacid orsome vitamin compounds. In other embodiments, the hydroxyl group of analcohol, hydroxyacid, hydroxyamino acid, or some vitamin compounds isconjugated to the C-3 of dextrorphan. In further embodiments, ahydroxyacid is used as a linker that is connected to the C-3 ofdextrorphan on one end (by reaction with its hydroxyl group) and to analcohol, hydroxyacid, hydroxyamino acid, or vitamin compound on theother end (by reaction with its carboxyl group). In yet furtherembodiments, a dicarboxylic acid is used as a linker that is connectedto the C-3 of dextrorphan on one end and to an alcohol, hydroxyacid,hydroxyamino acid, or vitamin compound on the other end. In someembodiments, the chemical connection between dextrorphan and theoxoacids, polyethylene glycols, and/or vitamin compounds can beestablished through an N-alkyl linker by an alkylation reaction at theN-17 tertiary amine of dextrorphan to form a quaternary ammonium salt ordextrorphanium salt. In some embodiments, the oxoacids, polyethyleneglycols, and/or vitamin compounds are directly connected to this N-alkyllinker. In other embodiments, a second linker is attached to the firstN-alkyl linker, and the oxoacids, polyethylene glycols, and/or vitamincompounds are directly connected to the second linker. In furtherembodiments, the second linker may comprise an alcohol, hydroxyacid, orhydroxyamino acid.

The use of the term “dextrorphan” herein means the (+)-isomer of17-methylmorphinan-3-ol, including all salt forms thereof. In someembodiments, the conjugates contain dextrorphan in a racemic mixture(racemorphan). In other embodiments, the dextrorphan conjugates are notin a racemic mixture. Depending on the chemical structure of the linkersand oxoacids, polyethylene glycol (PEG or PEO), and/or vitamincompounds, as well as the chiral composition of the dextrorphan to whichthey are attached, the resulting prodrug conjugates can be opticallyactive mixtures of isomers, racemic mixtures, single isomers orcombinations thereof.

As used herein, the term “conjugate” means a compound or substanceformed by bonding two or more chemical compounds or substances in such away that the bonding is reversible in vivo. For example, a conjugate isthe resultant compound formed by bonding at least one pharmaceutical ortherapeutically active ingredient with at least one ligand, such as atleast one oxoacid, or other substance or compound capable of being aligand, which is then broken down in vivo into the pharmaceutical ortherapeutically active ingredient and ligand. One skilled in the artwill appreciate that the term “conjugate” is used in a non-limitingmanner and includes various forms including salts, polymorphs, amongothers.

As used herein, “normative patient” as used herein means a patient that,in general, meets or requires standard and/established treatmentmodalities, treatment guidelines, prescribing guidelines, among othersto achieve a variety of pharmaceutical and/or therapeutic outcomes.

As used herein, the term “prodrug” refers to a substance converted froman inactive or less active form of a drug to an active drug in the bodyby a chemical or biological reaction. In the present technology, theprodrug is a conjugate of at least one drug, dextrorphan, and at leastone oxoacid, for example. Thus, the conjugates of the present technologyare prodrugs and the prodrugs of the present technology are conjugates.

Prodrugs are often useful because, in some embodiments, they may beeasier to administer or process than the parent drug. They may, forinstance, be more bioavailable by oral administration whereas the parentdrug is not. The prodrug may also have improved solubility inpharmaceutical compositions over the parent drug. An embodiment of aprodrug would be a dextrorphan conjugate that is metabolized to revealthe active moiety. In certain embodiments, upon in vivo administration,a prodrug is chemically converted to the biologically, pharmaceuticallyor therapeutically more active form of the compound. In certainembodiments, a prodrug is enzymatically metabolized by one or more stepsor processes to the biologically, pharmaceutically or therapeuticallyactive form of the compound. To produce a prodrug, a pharmaceuticallyactive compound is modified such that the active compound will beregenerated upon in vivo administration. The prodrug is designed toalter the metabolism, pharmacokinetics, or the transport characteristicsof a drug in certain embodiments, to reduce or lessen side-effects ortoxicity, to improve bioavailability and/or water solubility, to improvethe flavor of a drug or to alter other characteristics or properties ofa drug in other discrete embodiments.

In some embodiments, the present technology provides at least oneprodrug composition comprising at least one conjugate. The at least oneconjugate may comprise at least one dextrorphan and at least oneoxoacid, polyethylene glycol, vitamin compound, derivatives thereof, orcombinations thereof. In some embodiments, the conjugate furthercomprises at least one linker. The linker chemically bonds thedextrorphan to the oxoacid, polyethylene glycol, or vitamin compound viaone or more covalent bonds.

Depending on the linker and/or the oxoacid, polyethylene glycol, orvitamin compound conjugated to dextrorphan or derivative thereof, the atleast one prodrug or conjugate formed can be either a neutral(uncharged), a free acid, a free base or a pharmaceutically acceptableanionic salt form or salt mixtures with any ratio between positive andnegative components. These anionic salt forms can include, but are notlimited to, for example, acetate, l-aspartate, besylate, bicarbonate,carbonate, d-camsylate, l-camsylate, citrate, edisylate, formate,fumarate, gluconate, hydrobromide/bromide, hydrochloride/chloride,d-lactate, i-lactate, d,l-lactate, d,l-malate, l-malate, mesylate,pamoate, phosphate, succinate, sulfate, bisulfate, d-tartrate,l-tartrate, d,l-tartrate, meso-tartrate, benzoate, gluceptate,d-glucuronate, hybenzate, isethionate, malonate, methylsulfate,2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate,thiocyanate, acefyllinate, aceturate, aminosalicylate, ascorbate,borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate,cholate, cypionate, dichloroacetate, edentate, ethyl sulfate, furate,fusidate, galactarate (mucate), galacturonate, gallate, gentisate,glutamate, glutarate, glycerophosphate, heptanoate (enanthate),hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate,lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate,napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate,pyrophosphate, salicylate, salicylsulfate, sulfosalicylate, tannate,terephthalate, thiosalicylate, tribrophenate, valerate, valproate,adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate,glycolate, thiocyanate, or undecylenate.

Without wishing to be limited to the following theory, it is believedthat the prodrugs/conjugates of the present technology undergo enzymehydrolysis of the ligand/linker-dextrorphan bond(s) in vivo, whichsubsequently leads to a cascade reaction resulting in rapid regenerationof dextrorphan and the respective oxoacid, polyethylene glycol, vitamincompound, or metabolites thereof and/or derivatives thereof. Theoxoacids, polyethylene glycols, vitamin compounds, or derivativesthereof, of the present technology are non-toxic or have very lowtoxicity at the given dose levels and are preferably known drugs,natural products, metabolites, or GRAS (Generally Recognized As Safe)compounds (e.g., preservatives, dyes, flavors, etc.) or non-toxicmimetics or derivatives thereof.

General Structures

In some embodiments, the general structure of the conjugates ofdextrorphan of the present technology can be represented by thefollowing general Formula IA:

-   -   where L¹ is absent, or

-   -   Y¹ is absent, or [A-X—Z]_(n)    -   where A, X, Z are independently absent or selected from —O—, —S—        or —(CR¹R²)_(k)—    -   R¹, R² are independently selected from H, alkyl, aryl,        alkylaryl, alkoxy, haloalkyl, or haloaryl    -   n and k are independently 1-4    -   G_(m) ¹ is absent or selected independently for each repeating        subunit from H, oxoacid, polyethylene glycol having from 2 to 5        ethylene oxide units, or a vitamin compound, and m is 1-4,        except that m is 1 when G¹ is a hydrogen atom;    -   or a pharmaceutically acceptable salt thereof.

In some embodiments, L¹ and Y¹ are absent, G¹ is one or more oxoacids,and m is 1-3. Representative examples include, but are not limited to3-Val-dextrorphan; 3-(N-acetyl-Val)-dextrorphan;3-(ValValPhe)-dextrorphan; 3-(PhePhePhe)-dextrorphan;3-(AlaAlaVal)-dextrorphan; 3-(GlyGlyAla)-dextrorphan;3-hippuryl-dextrorphan; 3-(ProProPhe)-dextrorphan;3-(GlyGly)-dextrorphan; 3-(ValGly)-dextrorphan; 3-(AlaPro)-dextrorphan;3-cinnamoyl-dextrorphan; 3-(N,O-diacetyl-Tyr)-dextrorphan; and3-(N-succinoyl-Val)-dextrorphan;

In some embodiments, L¹ is present, A and Z are 0, X is —(CR¹R²)_(k)—,and G¹ is one or more oxoacids and m is 1-3. Representative examplesinclude, but are not limited to, 3-(N-acetyl-Val-OCH₂OC(O))-dextrorphan;3-(cinnamoyl-OCH₂OC(O))-dextrorphan; 3-(benzoyl-OCH₂OC(O)-dextrorphan;3-(butanoyl-OCH₂OC(O))-dextrorphan;3-(N,O-acetyl-Lys-OCH₂OC(O))-dextrorphan.

In some embodiments, L¹ and Y¹ are absent, and G¹ is a vitamin compound.Representative examples include, but are not limited to,3-biotinyl-dextrorphan.

In some embodiments, L¹ is present, A is O, X and Z are absent, and G¹is a vitamin compound. Representative examples include, but are notlimited to, 3-(ascorbyl-C(O))-dextrorphan.

In some embodiments, L¹ is present, Y¹ is absent, m is 2 and G_(m) ¹ canbe represented as G^(1a) and G^(1b) where G^(1a) is a hydroxycarboxylicacid, and G^(1b) is a vitamin compound. Representative examples include,but are not limited to 3-(biotinyl-glycoloyl)-dextrorphan.

In some embodiments, L¹ is absent, Y¹ is absent, m is 2 and G_(m) ¹ canbe represented as G^(1a) and G^(1b) where G^(1a) is a dicarboxylic acid,and G^(1b) is a vitamin compound. Representative examples include, butare not limited to 3-(thiaminyl-succinoyl)-dextrorphan.

In some embodiments, L¹ is present, A is —CR¹R²—, X is absent, Z is—CR¹R²— or absent, and G¹ is polyethylene glycol. Representativeexamples include but are not limited to3-(N₃-PEG₄-CH₂CH₂C(O))-dextrorphan and3-(H₂N-PEG₅-CH₂CH₂C(O))-dextrorphan.

In some embodiments, L¹ is present, A is oxygen, X and Z are—(CR¹R²)_(k)— and G¹ is a hydrogen atom. Representative examplesinclude, but are not limited to, 3-(ethoxy-C(O))-dextrorphan.

In some embodiments, L¹ is present, A is —(CR¹R²)_(k)—, X is oxygen (O),Z is absent, and G¹ is acetic acid. Representative examples include butare not limited to 3-(acetyl-OCH₂C(O))-dextrorphan and3-(acetyl-OCH(phenyl)C(O))-dextrorphan.

In some embodiments, the general structure of the conjugates ofdextrorphan of the present technology can be represented by thefollowing general Formula IB:

-   -   where L² is absent, or is

-   -   Y² is absent, or [A-X—Z]_(n)    -   where A, X, Z are independently absent or selected from —O—, —S—        or —(CR¹R²)_(k)—    -   J is [M-W]_(p)    -   where M is absent, or —(CR³R⁴)_(q)—; and W is absent, or —O— or        —S—    -   R¹, R², R³, R⁴ are each independently selected from H, alkyl,        aryl, alkylaryl, alkoxy, haloalkyl, or haloaryl    -   n and k are independently 1-4    -   p and q are independently 1-4    -   G_(m) ² is absent or selected independently for each repeating        subunit from H, oxoacid, polyethylene glycol having from 1 to 5        ethylene oxide units, or a vitamin compound, and m is 1-4,        except that m is 1 when G² is a hydrogen atom;    -   or a pharmaceutically acceptable salt thereof.

In some embodiments, M is —(CR³R⁴)_(q)—, W, L² and Y² are absent, G² isan oxoacid, and m is 1-3. Representative examples include, but are notlimited to N-(acetyl-OCH₂)-dextrorphanium;N-(pivaloyl-OCH₂)-dextrorphanium; N-(Ser-Ile-CH₂)-dextrorphanium;N-(Val-CH₂)-dextrorphanium; and N-(Phe-Val-CH₂)-dextrorphanium.

In some embodiments, M is —(CR³R⁴)_(q)—, W is —O—, L² is present, A is—CR¹R²—, X is absent, Z is absent or —CR¹R²—, G² is polyethylene glycol.Representative examples include but are not limited toN-(MeO-PEG₃-CH₂C(O)OCH₂)-dextrorphanium andN—(HO-PEG₄-CH₂CH₂C(O)CH₂)-dextrorphanium.

In some embodiments, M is —(CR³R⁴)_(q)—, W is —O—, L² is present, A andZ are —O—, X is —(CR¹R²)_(k)—, G² is an oxoacid, and m is 1-3.Representative examples include but are not limited toN—(BzO-CH₂OC(O)OCH₂)-dextrorphanium;N-(Ala-CH₂OC(O)OCH₂)-dextrorphanium; andN-(Pro-Val-CH₂OC(O)OCH₂)-dextrorphanium.

In some embodiments, M is —(CR³R⁴)_(q)—, W is —O—, L² is present, A is—O—, X and Z are absent, G² is a vitamin compound, and m is 1-3.

In some embodiments, the general structure of the conjugates ofdextrorphan of the present technology can be represented by thefollowing general Formula IC:

-   -   where L¹ and L² are independently absent, or

-   -   Y¹ and Y² are independently either absent, or [A-X—Z]_(n)    -   where A, X, Z are independently selected for Y¹ and Y², and are,        independent of each other, either absent or selected from the        group of —O—, —S—, or —(CR¹R²)_(k)—    -   J is [M-W]_(p)    -   where M is absent, or —(CR³R⁴)_(q)—; and W is absent, or —O— or        —S—    -   R¹ and R² are each independently selected for Y¹ and Y², and        are, independent of each other, selected from H, alkyl, aryl,        alkylaryl, alkoxy, haloalkyl, or haloaryl    -   R³ and R⁴ are each independently selected from H, alkyl, aryl,        alkylaryl, alkoxy, haloalkyl, or haloaryl    -   for each Y¹ and Y², n is independently an integer of 1-4    -   for each repeating unit of [A-X—Z]_(n), when (CR¹R²)_(k) is        present, k is independently an integer of 1-4.    -   p and q are independently 1-4    -   G_(m) ¹ and G_(m) ² are independently absent, or selected        independently of each other and, when present, each repeating        subunit is independently selected from H, oxoacid, polyethylene        glycol having from 2 to 5 ethylene oxide units, or a vitamin        compound;    -   where m is selected independently for G¹ and G², and is an        integer of 1-4, except that m is 1 when G¹ or G² is a hydrogen        atom;    -   or a pharmaceutically acceptable salt thereof.

In some embodiments, L¹ and Y¹ are absent, G¹ is one or more oxoacids,and m is 1-3, and M is —(CR³R⁴)_(q)—; W is O or absent, L² and Y² areabsent, G² is one or more oxoacids, and m is 1-3. Representativeexamples include 3-(pivaloyl)-N-(pivaloyl-OCH₂)-dextrorphanium;3-(Ac-Val)-N-(Phe-Phe-CH₂)-dextrorphanium;3-(Ser-Ile)-N-(Val-CH₂)-dextrorphanium;3-Val-N-(Val-CH₂)-dextrorphanium;3-acetyl-N-(acetyl-OCH₂)-dextrorphanium.

In some embodiments, L¹ and Y¹ are present, A is O, X is —(CR¹R²)_(k)—,Z is O, G¹ is one or more oxoacids, and m is 1-3, and M is—(CR³R⁴)_(q)—; W is O or absent, L² and Y² are absent, G² is one or moreoxoacids, and m is 1-3. Representative examples include3-(acetylsalicyloyl-OCH₂OC(O))—N—(Ac-Val-CH₂)-dextrorphanium.

In some embodiments, L¹ is present, Y¹ is present, where A is O, X and Zare —(CR¹R²)_(k)—, and G¹ is H, and M is —(CR³R⁴)_(q)—, W is O, L² andY² are present, where A is O, X and Z are —(CR¹R²)_(k)—, and G² is H.Representative examples include3-(ethoxy-C(O))—N-(ethoxy-C(O)CH(CH₃))-dextrorphanium.

Oxoacids

Organic oxoacids (i.e., oxyacids, oxo acids, oxy-acids, oxiacids,oxacids) of the present technology are a class of compounds whichcontain oxygen, at least one other element, and at least one hydrogenbound to oxygen, and which produce a conjugate base by loss of positivehydrogen ion(s) (protons). Organic acids include carboxylic acids.Carboxylic acids are widespread in nature (naturally occurring), butcarboxylic acids can also be non-natural (synthetic). Carboxylic acidscan be categorized into numerous classes based on their molecularstructure or formula, and many of the different classes may overlap.

Without wishing to limit the scope to one classification, the carboxylicacids of the present technology can be grouped into the followingcategories: aryl carboxylic acids, aliphatic carboxylic acids,dicarboxylic, polycarboxylic acids, and amino acids.

Some embodiments of the present technology provide oxoacids conjugatedto dextrorphan, where the carboxylic acid group is directly attached toan aryl moiety. Carboxylic acids directly attached to the aryl moietyinclude benzoates and heteroaryl carboxylic acids. Benzoates are commonin nature and include, for example but are not limited to,aminobenzoates (e.g., anthranilic acid analogs such as fenamates),aminohydroxybenzoates and hydroxybenzoates (e.g., salicylic acidanalogs).

The general structure of benzoic acid and benzoic acid derivatives ofthe present technology can be represented by the following Formula II:

In this Formula II, R¹, R², R³ are independently selected from the groupconsisting of H, hydroxyl, amino, amine, amide, thiol, cyano, nitro,halogen, imine, alkyl, alkoxy, aryl, alkenyl, alkynyl, haloalkyl,alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl,cycloalkynyl, carbonyl, thioether, selenoether, silyl, silyloxy,sulfonyl, and phosphonate.

Suitable hydroxyobenzoic acids can be found in FIG. 1 and include, butare not limited to, benzoic acid, salicylic acid, acetylsalicylic acid(aspirin), 3-hydroxybenzoic acid, 4-hydroxybenzoic acid,6-methylsalicylic acid, o,m,p-cresotinic acid, anacardic acids,4,5-dimethylsalicylic acid, o,m,p-thymotic acid, diflunisal,o,m,p-anisic acid, 2,3-dihydroxybenzoic acid (2,3-DHB), α,β,γ-resorcylicacid, protocatechuic acid, gentisic acid, piperonylic acid,3-methoxysalicylic acid, 4-methoxysalicylic acid, 5-methoxysalicylicacid, 6-methoxysalicylic acid, 3-hydroxy-2-methoxybenzoic acid,4-hydroxy-2-methoxybenzoic acid, 5-hydroxy-2-methoxybenzoic acid,vanillic acid, isovanillic acid, 5-hydroxy-3-methoxybenzoic acid,2,3-dimethoxybenzoic acid, 2,4-dimethoxybenzoic acid,2,5-dimethoxybenzoic acid, 2,6-dimethoxybenzoic acid, veratric acid(3,4-dimethoxybenzoic acid), 3,5-dimethoxybenzoic acid, gallic acid,2,3,4-trihydroxybenzoic acid, 2,3,6-trihydroxybenzoic acid,2,4,5-trihydroxybenzoic acid, 3-O-methylgallic acid (3-OMGA),4-O-methylgallic acid (4-OMGA), 3,4-O-dimethylgallic acid, syringicacid, 3,4,5-trimethoxybenzoic acid.

Suitable aminobenzoic acids are shown in FIG. 2 and include, but are notlimited to, anthranilic acid, 3-aminobenzoic acid,4,5-dimethylanthranilic acid, N-methylanthranilic acid,N-acetylanthranilic acid, fenamic acids (e.g., tolfenamic acid,mefenamic acid, flufenamic acid), 2,4-diaminobenzoic acid (2,4-DABA),2-acetylamino-4-aminobenzoic acid, 4-acetylamino-2-aminobenzoic acid,2,4-diacetylaminobenzoic acid.

Suitable aminohydroxybenzoic acids include, but are not limited to,4-aminosalicylic acid, 3-hydroxyanthranilic acid, 3-methoxyanthranilicacid.

In some embodiments, the composition includes a benzoate conjugatecomprising at least one dextrorphan conjugated to at least one benzoicacid or benzoic acid derivative, salt thereof or combination thereof.

In some embodiments, the benzoates include numerous benzoic acidanalogs, benzoate derivatives with hydroxyl or amino groups or acombination of both. The hydroxyl and amino functions may be present intheir free form or capped with another chemical moiety, preferably butnot limited to methyl or acetyl groups. The phenyl ring may haveadditional substituents, but the total number of substituents can befour or less, three or less, or two or less.

In yet another embodiment, the present technology provides a prodrug orcomposition comprising at least one conjugate of dextrorphan and atleast one heteroaryl carboxylic acid, a derivative thereof, or acombination thereof. The heteroaryl carboxylic acid can be selected fromFormula III, Formula IV, Formula V, Formula VI, Formula VII, FormulaVIII, Formula IX, Formula X, or Formula XI, where Formula III, FormulaIV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX,Formula X, or Formula XI are:

For these Formulas III, IV, V, VI, VII, VIII, IX, X, and XI, R¹, R², R³are independently selected from the group consisting of H, hydroxyl,amino, amine, amide, thiol, cyano, nitro, halogen, imine, alkyl, alkoxy,aryl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, heterocycle,arylalkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, carbonyl, thioether,selenoether, silyl, silyloxy, sulfonyl, and phosphonate. Some structuresof suitable heteroaryl carboxylic acids for use in the presenttechnology are found in FIG. 3.

In some embodiments, the carboxy group of the aryl carboxylic acids canbe attached directly to the aromatic ring. The present technologyincludes both carbon-only aryl groups and aryl groups with heteroatoms(heteroaryl). The aryl or heteroaryl group which is connected directlyto the carboxyl function can be a 6-membered ring and contains no or oneheteroatom. In some embodiments, the additional substituted orunsubstituted aromatic or aliphatic rings can be fused to this6-membered aryl or heteroaryl moiety. In some embodiments, the arylcarboxylic acids may have only one free carboxylic acid group and thetotal number of phenyl substituents on the 6-membered ring should befour or less, for example, 4, 3, 2 or 1.

Phenylacetates

In some embodiments of the present technology, the aryl carboxylic acidsof the present technology comprise a carboxylic group that is separatedby one carbon from the aryl moiety. These aryl carboxylic acids includebranched phenylpropionic acids (i.e., 2-methyl-2-phenylacetates) orother derivatives of phenylacetate (FIG. 4). The general structure of atleast one phenylacetate of the present technology is represented by thefollowing general Formula XII:

For this Formula XII, R¹, R², R³, R⁴, R⁵ are independently selected fromthe group consisting of H, hydroxyl, amino, amine, amide, thiol, cyano,nitro, halogen, imine, alkyl, alkoxy, aryl, alkenyl, alkynyl, haloalkyl,alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl,cycloalkynyl, carbonyl, thioether, selenoether, silyl, silyloxy,sulfonyl, and phosphonate.

Phenylacetic acids encompass various subsets of natural products,metabolites and pharmaceuticals. One such pharmaceutically importantsubset is “profens”, a type of NSAIDs and derivatives of certainphenylpropionic acids (e.g., 2-methyl-2-phenylacetic acid analogs). Someother phenylacetates have central functions in the phenylalanine andtyrosine metabolism.

Some examples of phenylacetates of the present technology include, butare not limited to, phenylacetic acid (hydratropic acid),2-hydroxyphenylacetic acid, 3-hydroxyphenylacetic acid,4-hydroxyphenylacetic acid, homoprotocatechuic acid, homogentisic acid,2,6-dihydroxyphenylacetic acid, homovanillic acid, homoisovanillic acid,homoveratric acid, atropic acid, d,l-tropic acid, diclofenac,d,l-mandelic acid, 3,4-dihydroxy-d,l-mandelic acid,vanillyl-d,l-mandelic acid, isovanillyl-d,l-mandelic acid, ibuprofen,fenoprofen, carprofen, flurbiprofen, ketoprofen, and naproxen. Somestructures of suitable phenylacetates for use in the present technologyare found in FIG. 4.

Benzylacetates

In additional embodiments, the aryl carboxylic acids of the presenttechnology comprise a carboxylic group that is separated by two carbonsfrom the aryl moiety. These aryl carboxylic acids include benzylacetates(FIG. 5) and substituted derivatives thereof and analogs of cinnamicacid (FIG. 6). Both classes of compounds are abundant in nature in theform of natural products or metabolites (e.g., phenylalaninemetabolism). The general structures of some benzylacetates andcinnamates of the present technology are represented by the followinggeneral Formulas XIII and XIV:

For these Formulas XIII and XIV, R¹, R², R³, R⁴, R⁵, R⁶ areindependently selected from the group consisting of H, hydroxyl, amino,amine, amide, thiol, cyano, nitro, halogen, imine, alkyl, alkoxy, aryl,alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, heterocycle,arylalkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, carbonyl, thioether,selenoether, silyl, silyloxy, sulfonyl, and phosphonate.

Benzylacetic acids are defined by an ethylene group between the carboxylfunction and the phenyl ring. Both the alkyl chain and the aryl moietycan have substituents, preferably hydroxyl groups. Some compounds ofthis class can be found in the phenylalanine metabolism.

Some examples of benzylacetates of the present technology include, butare not limited to, benzylacetic acid, melilotic acid,3-hydroxyphenylpropanoic acid, 4-hydroxyphenylpropanoic acid,2,3-dihydroxyphenylpropanoic acid, d,l-phenyllactic acid,o,m,p-hydroxy-d,l-phenyllactic acid, or phenylpyruvic acid.

Cinnamates

Cinnamic acids (3-phenylacrylic acids) (FIG. 6) are unsaturated analogsof benzylacetic acids. Cinnamates occur in two isomeric forms: cis (Z)and trans (E). The cinnamate isomers of certain embodiments of thepresent technology are preferably, but not limited to, the transconfiguration. Similar to benzylacetates, derivatives of cinnamic acidcan be substituted on the alkenyl or aryl moiety of the molecule.Preferred substituents of some embodiments of the present technology arehydroxyl and methoxy groups. Certain cinnamates are thought to play akey role in phenylalanine metabolism.

Some examples of cinnamates of the present technology include, but arenot limited to, cinnamic acid, o,m,p-coumaric acid,2,3-dihydroxycinnamic acid, 2,6-dihydroxycinnamic acid, caffeic acid,ferulic acid, isoferulic acid, 5-hydroxyferulic acid, sinapic acid, or2-hydroxy-3-phenylpropenoic acid.

Suitable aliphatic carboxylic acids for use in the present technologyinclude, but are not limited to, for example, saturated,monounsaturated, polyunsaturated, acetylenic, substituted (e.g., alkyl,hydroxyl, methoxy, halogenated, etc.), heteroatom containing or ringcontaining carboxylic acids. Suitable examples of saturated carboxylicacids include, but are not limited to, for example, methanoic, ethanoic,propanoic, butanoic, pentanoic, hexanoic, heptanoic, octanoic,2-propylpentanoic acid, nonanoic, decanoic, dodecanoic, tetradecanoic,hexadecanoic, heptadecanoic, octadecanoic, or eicosanoic acid. Suitablemonounsaturated carboxylic acids for practice of the present technologyinclude, but are not limited to, for example, 4-decenoic, 9-decenoic,5-lauroleic, 4-dodecenoic, 9-tetradecenoic, 5-tetradecenoic,4-tetradecenoic, 9-hexadecenoic, 6-hexadecenoic, 6-octadecenoic, or9-octadecenoic acid.

Suitable polyunsaturated carboxylic acids for use in the presenttechnology include, but are not limited to, for example, sorbic,octadecadienoic, octadecatrienoic, octadecatetraenoic, eicosatrienoic,eicosatetraenoic, eicosapentaenoic, docosapentaenoic, or docosahexaenoicacids. Suitable acetylenic carboxylic acids for use in the presenttechnology include, but are not limited to octadecynoic, octadecenynoic,6,9-octadecenynoic, heptadecenynoic, tridecatetraenediynoic,tridecadienetriynoic, octadecadienediynoic, heptadecadienediynoic,octadecadienediynoic, octadecenediynoic, or octadecenetriynoic acids.

Suitable substituted carboxylic acids for practice of the presenttechnology include, but are not limited to, for example,methylpropanoic, isovaleric, methylhexadecanoic, 8-methyl-6-nonenoic,methyloctadecanoic, trimethyloctacosanoic, trimethyltetracosenoic,heptamethyltriacontanoic, tetramethylhexadecanoic,tetramethylpentadecanoic, lactic, glyceric, glycolic, threonic,3-hydroxypropionic, hydroxyoctadecatrienoic, hydroxyoctadecenoic,hydroxytetracosanoic, 2-hydroxybutyric, 3-hydroxybutyric,4-hydroxybutyric, 4-hydroxypentanoic, hydroxyoctadecadienediynoic,hydroxyoctadecadienoic, 10-hydroxydecanoic, hydroxydecenoic,hydroxyeicosenoic, hydroxyeicosadienoic, hydroxyhexadecanoic,dihydroxytetracosenoic, dihydroxydocosanoic, hydroxydocosanoic,trihydroxyoctadecanoic, trihydroxyhexadecanoic,trihydroxyicosahexaenoic, trihydroxyicosapentaenoic,2-methoxy-5-hexadecenoic, 2-methoxy hexadecanoic,7-methoxy-4-tetradecenoic, 9-methoxypentadecanoic,11-methoxyheptadecanoic, 3-methoxydocosanoic, diacetoxydocosanoic,2-acetoxydocosanoic, 2-acetoxytetracosanoic, 2-acetoxyhexacosanoic,9-oxononanoic, oxodecanoic, oxododecenoic, hydroxyoxodecenoic,10-oxo-8-decenoic, fluorooctadecenoic, fluorodecanoic,fluorotetradecanoic, fluorohexadecanoic, fluorooctadecadienoic,chlorohydroxyhexadecanoic, chlorohydroxyoctadecanoic,dichlorooctadecanoic, 3-bromo-2-nonaenoic, 9,10-dibromooctadecanoic,9,10,12,13-tetrabromooctadecanoic, 10-nitro-9,12-octadecadienoic,12-nitro-9,12-octadecadienoic, 9-nitro-9-octadecenoic, 9-oxo-2-decenoic,9-oxo-13-octadecenoic, oxooctadecatrienoic, 15-oxo-18-tetracosenoic,17-oxo-20-hexacosenoic, or 19-oxo-22-octacosenoic acids.

Suitable examples of heteroatom containing carboxylic acids include, butare not limited to, for example, 9-(1,3-nonadienoxy)-8-nonenoic,9-(1,3,6-nonatrienoxy)-8-nonenoic, 12-(1-hexenoxy)-9,11-dodecadienoic,12-(1,3-hexadienoxy)-9,11-dodecadienoic, 2-dodecylsulfanylacetic,2-tetradecylsulfanylacetic, 3-tetradecylsulfanylprop-2-enoic, or3-tetradecylsulfanylpropanoic acid. Suitable examples of ring containingcarboxylic acids include, but are not limited to, for example,10-(2-Hexylcyclopropyl)decanoic,3-(2-[6-bromo-3,5-nondienylcyclopropyl)propanoic,9-(2-hexadecylcyclopropylidene)non-5-enoic,8-(2-octyl-1-cyclopropenyl)octanoic,7-(2-octyl-1-cyclopropenyl)heptanoic, 9,10-epoxyoctadecanoic,9,10-epoxy12-octadecenoic, 12,13-epoxy-9-octadecenoic,14,15-epoxy-11-eicosenoic, 11-(2-cyclopenten-1-yl)undecanoic,13-(2-cyclopenten-1-yl)tridecanoic, 13-(2-cyclopentenyl)-6-tridecenoic,11-cyclohexylundecanoic, 13-cyclohexyltridecanoic,7-(3,4-dimethyl-5-pentylfuran-2-yl)heptanoic,9-(4-methyl-5-pentylfuran-2-yl)nonanoic, 4-[5]-ladderane-butanoic,6-[5]-ladderane-hexanoic, or 6-[3]-ladderane-hexanoic acid.

In some embodiments, the dextrorphan, derivatives thereof orcombinations thereof, can be conjugated to one or more dicarboxylicacids or tricarboxylic acids. Dicarboxylic acids are compounds with twocarboxyl groups with a general formula of HOOC—R—COOH, where R can be analkyl, alkenyl, alkynyl or aryl group, or derivatives thereof.Dicarboxylic acids can have straight carbon chains or branched carbonchains. The carbon chain length may be short or long. Polycarboxylicacids are carboxylic acids with three or more carboxyl groups. Suitableexamples of dicarboxylic and tricarboxylic acids for the practice of thepresent technology include, but are not limited to, for example, oxalic,malonic, succinic, glutaric, adipic, pimelic, suberic, azelaic, sebacic,brassylic, thapsic, malic, tartaric, dihydroxymesoxalic,D-hydroxyglutaric, methylmalonic, meglutol, diaminopimelic, carbamoylaspartic, fumaric, maleic, mesaconic, 3-methylglutaconic, traumatic,phthalic acid, isophthalic, terephthalic, dipicolinic, citric acid,isocitric, carballylic, or trimesic acid. Some structures of suitabledicarboxylic acids for use in the practice of the present technology canbe found in FIG. 7, and some structures of suitable tricarboxylic acidsfor use in the practice of the present technology can be found in FIG.8.

Amino Acids

Amino acids are one of the most important building blocks of life. Theyconstitute the structural subunit of proteins, peptides, and manysecondary metabolites. In addition to the 22 standard (proteinogenic)amino acids that make up the backbone of proteins, there are hundreds ofother natural (non-standard) amino acids that have been discoveredeither in free form or as components in natural products. The aminoacids used in some embodiments of the prodrugs of this invention includenatural amino acids, synthetic (non-natural, unnatural) amino acids, andtheir derivatives.

Standard Amino Acids

There are currently 22 known standard or proteinogenic amino acids thatmake up the monomeric units of proteins and are encoded in the geneticcode. The standard amino acids include alanine, arginine, asparagine,aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine,isoleucine, leucine, lysine, methionine, phenylalanine, proline,pyrrolysine, selenocysteine, serine, threonine, tryptophan, tyrosine andvaline. These standard amino acids have the general structure shown inFIG. 9, where R represents the side chain on the α-carbon.

Non-Standard Amino Acids

Non-standard amino acids can be found in proteins created by chemicalmodifications of standard amino acids already incorporated in theproteins. This group also includes amino acids that are not found inproteins but are still present in living organisms either in their freeform or bound to other molecular entities. Non-standard amino acidsoccur mostly as intermediates in metabolic pathways of standard aminoacids and are not encoded by the genetic code. Examples of non-standardamino acids include but are not limited to ornithine, homoarginine,citrulline, homocitrulline, homoserine, theanine, γ-aminobutyric acid,6-aminohexanoic acid, sarcosine, cartinine, 2-aminoadipic acid,pantothenic acid, taurine, hypotaurine, lanthionine, thiocysteine,cystathionine, homocysteine, β-amino acids such as β-alanine,β-aminoisobutyric acid, β-leucine, β-lysine, β-arginine, β-tyrosine,β-phenylalanine, isoserine, β-glutamic acid, β-tyrosine, β-dopa(3,4-dihydroxy-L-phenylalanine), α,α-disubstituted amino acids such as2-aminoisobutyric acid, isovaline, di-n-ethylglycine, N-methyl acidssuch as N-methyl-alanine, L-abrine, hydroxy-amino acids such as4-hydroxyproline, 5-hydroxylysine, 3-hydroxyleucine,4-hydroxyisoleucine, 5-hydroxy-L-tryptophan, cyclic amino acids such as1-aminocyclopropyl-1-carboxylic acid, azetidine-2-carboxylic acid andpipecolic acid. Some structures of suitable non-standard amino acidsthat can be used in some embodiments of the prodrugs of this inventionare shown in FIG. 10.

Synthetic Amino Acids

Synthetic amino acids do not occur in nature and are preparedsynthetically. Examples include but are not limited to allylglycine,cyclohexylglycine, N-(4-hydroxyphenyl)glycine, N-(chloroacetyl)glyclineester, 2-(trifluoromethyl)-phenylalanine,4-(hydroxymethyl)-phenylalanine, 4-amino-phenylalanine,2-chlorophenylglycine, 3-guanidino propionic acid, 3,4-dehydro-proline,2,3-diaminobenzoic acid, 2-amino-3-chlorobenzoic acid,2-amino-5-fluorobenzoic acid, allo-isoleucine, tert-leucine,3-phenylserine, isoserine, 3-aminopentanoic acid, 2-amino-octanedioicacid, 4-chloro-p-phenylalanine, P-homoproline, P-homoalanine,3-amino-3-(3-methoxyphenyl)propionic acid, N-isobutyryl-cysteine,3-amino-tyrosine, 5-methyl-tryptophan, 2,3-diaminopropionic acid,5-aminovaleric acid, and 4-(dimethylamino)cinnamic acid. Some structuresof suitable synthetic amino acids that can be used in some embodimentsof the prodrugs of this invention are shown in FIG. 11.

Polyethylene Glycols

In some embodiments of the present technology, dextrorphan, derivativesthereof or combinations thereof, is conjugated to a polyethylene glycol,or derivatives thereof. In some embodiments, the terminal hydroxyl groupof the polyethylene glycol can be substituted with an amino, azide, ormethoxy group. Some suitable structures of polyethylene glycols includethe following:

wherein k is 1-20 for these structures.

Vitamin Compounds

In some embodiments of the present technology, dextrorphan, derivativesthereof, or combinations thereof, is conjugated to one or more vitamincompounds. The vitamin compounds include both water soluble and fatsoluble vitamins or derivatives thereof. Useful vitamin compounds arethose that have one or more carboxylic acid groups, one or more hydroxylgroups, or one or more other reactive functional groups that can form abond with dextrorphan either directly or through one or more linkers.Examples of water soluble vitamins that could be conjugated todextrorphan include biotin, folate (folic acid), niacin, pantothenicacid, riboflavin, thiamin, pyridoxine, and ascorbic acid. Examples offat soluble vitamins that could be conjugated to dextrorphan includeVitamin A (retinol), vitamin D₂ (ergocalciferol), vitamin D₃(cholecalciferol), vitamin E (tocopherols and tocotrienols, includingalpha, beta, gamma, and delta-tocopherol), and vitamin K(phylloquinone). Some structures of suitable water soluble vitamins andfat soluble vitamins for use in the present technology are found inFIGS. 12A and 12B, respectively.

Linkers

In some embodiments of the present technology, the dextrorphan,derivatives thereof, or combinations thereof, is conjugated to one ormore organic oxoacids, polyethylene glycols, or vitamin compounds viaone or more linkers. Linker moieties of the present technology, whichconnect the one or more organic oxoacids, polyethylene glycols, orvitamin compounds to the dextrorphan, derivatives thereof orcombinations thereof, can have the following general formulas:

—C(O)O—X—O— or —C(O)X—O—X or —C(O)O—X— or C(O)X—O—

-   -   for conjugation at the C-3 hydroxyl position;

—X— or —X—O—

-   -   for conjugation at the N-17 tertiary amine position;        wherein for these linker formulas, X is selected from a        representative group including alkyl, substituted alkyl, aryl,        substituted aryl, arylalkyl, substituted alkylaryl, heteroalkyl,        substituted heteroalkyl, heteroaryl, substituted heteroaryl,        heterocycle, substituted heterocycle, alkenyl, substituted        alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted        cycloalkyl, cycloalkenyl, substituted cycloalkenyl,        cycloalkynyl, or substituted cycloalkynyl.

Preferred embodiments of the present technology include linkers where Xis at least one aliphatic group. More preferred embodiments includelinkers where X is at least one alkyl group.

Physiological Benefits

The above defined prodrugs or conjugates of dextrorphan can be givenorally and, upon administration, release the active dextrorphan afterbeing hydrolyzed in the body. Not to be bound by any particular theory,it is believed that since the oxoacids, polyethylene glycols, andvitamin compounds of this invention are naturally occurring metabolitesor mimetics thereof or pharmaceutically active compounds, these prodrugscan be easily recognized by physiological systems resulting inhydrolysis and release of dextrorphan. The claimed prodrugs themselvesare either not active or have limited pharmacological activity andconsequently may follow a metabolic pathway that differs from the parentdrug. By choosing suitable oxoacids, polyethylene glycols, and/orvitamin compounds (“ligands”), the release of dextrorphan into thesystemic circulation can be controlled even when the prodrug isadministered via routes other than oral. In one embodiment, the modifiedor conjugated dextrorphan would release dextrorphan similar to free orunmodified or unconjugated dextrorphan. In another embodiment, themodified or conjugated dextrorphan may have a more rapid release ofdextrorphan compared to unmodified or unconjugated dextrorphan. Inanother embodiment, the modified dextrorphan would be released in acontrolled or sustained manner. This controlled release can potentiallyalleviate certain side-effects and improve upon the safety profile ofthe parent drug. These side-effects may include, vomiting, drowsiness,nausea, dizziness, diarrhea, constipation, nervousness, restlessness,respiratory depression, hallucinations, double vision, hypotension,hypertension, blackouts, and skin rash. In addition, dextrorphan andother NMDA receptor antagonists are dissociative hallucinogens and arethus prone to substance abuse.

Recreational drug abuse of hallucinogens is a common problem. Dependingon the drug routes of administration may include oral, intranasal(“snorting”), and intravenous (“shooting”). In some embodiments,dextrorphan that is conjugated with a suitable ligand does not result inrapid spikes in plasma concentration after oral administration that issought by a potential drug abuser. In some embodiments, dextrorphanreleased from the conjugate may have a delayed T_(max) and possiblylower C_(max) than the parent drug. Not to be bound by any particulartheory, it is believed that the conjugates of the present technology,when taken orally or by other non-oral routes, reduce, lessen, or do notprovide the feeling of a “rush” even when taken orally at higher doses,but still maintain therapeutic relief. In another embodiment,dextrorphan conjugated with appropriate ligands of this invention is nothydrolyzed efficiently when administered via non-oral routes. As aresult, in some embodiments, the prodrugs of the present technology donot generate as high plasma or blood concentrations of releaseddextrorphan when injected or snorted compared to free dextrorphanadministered through these routes.

In some embodiments, the conjugates of the present technology, sincethey comprise ligands covalently bound to dextrorphan, are not able tobe physically manipulated to release the dextrorphan from the conjugateddextrorphan by methods, for example, of grinding up or crushing of solidforms.

In some embodiments, the at least one prodrug or conjugate of thepresent technology can be formulated into dosage forms that include butare not limited to tablet, capsule, caplet, troche, lozenge, powder,suspension, syrup, solution, oral thin film (OTF), oral strips,inhalation compounds or suppositories. In some embodiments, the dosageforms are administered orally. Preferred oral administration forms aresolutions, syrups, suspensions, capsules, tablets and OTF. Suitabledosing vehicles of the present technology include, but are not limitedto, water, phosphate buffered saline (PBS), Tween in water, and PEG inwater.

Solid dosage forms can optionally include one or more of the followingtypes of excipients: antiadherents, binders, coatings, disintegrants,gel-forming agents, fillers, flavors and colors, glidants, lubricants,preservatives, sorbents and sweeteners, among others.

Oral formulations of the present technology can also be included in asolution, a suspension or a slurry, in an aqueous liquid or anon-aqueous liquid. The formulation can be an emulsion, such as anoil-in-water liquid emulsion or a water-in-oil liquid emulsion. The oilscan be administered by adding the purified and sterilized liquids to aprepared enteral formula, which is then placed in the feeding tube of apatient who is unable to swallow.

Soft gel or soft gelatin capsules may be prepared, for example bydispersing the formulation in an appropriate vehicle (vegetable oils arecommonly used) to form a high viscosity mixture. This mixture is thenencapsulated with a gelatin based film using technology and machineryknown to those in the soft gel industry. The individual units so formedare then dried to constant weight.

Chewable tablets, for example, may be prepared by mixing theformulations with excipients designed to form a relatively soft,flavored, tablet dosage form that is intended to be chewed rather thanswallowed. Conventional tablet machinery and procedures, for example,direct compression and granulation, i.e., or slugging, beforecompression, can be utilized. Those individuals involved inpharmaceutical solid dosage form production are versed in the processesand the machinery used, as the chewable dosage form is a very commondosage form in the pharmaceutical industry.

Film coated tablets, for example may be prepared by coating tabletsusing techniques such as rotating pan coating methods or air suspensionmethods to deposit a contiguous film layer on a tablet.

Compressed tablets, for example may be prepared by mixing theformulation with one or more excipients intended to add bindingqualities to disintegration qualities. The mixture is either directlycompressed, or granulated and then compressed using methods andmachinery known to those in the industry. The resultant compressedtablet dosage units are then packaged according to market need, forexample, in unit dose, rolls, bulk bottles, blister packs, etc.

The present technology contemplates that the conjugates of the presenttechnology can be formulated into formulations or co-formulations thatmay further comprise one or more additional components. For example,such formulations can include biologically-acceptable carriers which maybe prepared from a wide range of materials. Without being limited to,such materials include diluents, binders and adhesives, lubricants,gel-forming agents, plasticizers, disintegrants, surfactants, colorants,bulking substances, flavorings, sweeteners and miscellaneous materialssuch as buffers and adsorbents in order to prepare a particularmedicated formulation.

Binders may be selected from a wide range of materials such ashydroxypropylmethylcellulose, ethylcellulose, or other suitablecellulose derivatives, povidone, acrylic and methacrylic acidco-polymers, pharmaceutical glaze, gums, milk derivatives, such as whey,starches, and derivatives, as well as other conventional binders knownto persons working in the art. Exemplary non-limiting solvents arewater, ethanol, isopropyl alcohol, methylene chloride or mixtures andcombinations thereof. Exemplary non-limiting bulking substances includesugar, lactose, gelatin, starch, and silicon dioxide.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations of the present technology can includeother suitable agents such as flavoring agents, preservatives andantioxidants. Such antioxidants would be food acceptable and couldinclude vitamin E, carotene, BHT or other antioxidants.

Other compounds which may be included by admixture are, for example,medically inert ingredients, e.g., solid and liquid diluents, such aslactose, dextrose, saccharose, cellulose, starch or calcium phosphatefor tablets or capsules, olive oil or ethyl oleate for soft capsules andwater or vegetable oil for suspensions or emulsions; lubricating agentssuch as silica, talc, stearic acid, magnesium or calcium stearate and/orpolyethylene glycols; gelling agents such as colloidal clays; thickeningagents such as gum tragacanth or sodium alginate, binding agents such asstarches, arabic gums, gelatin, methylcellulose, carboxymethylcelluloseor polyvinylpyrrolidone; disintegrating agents such as starch, alginicacid, alginates or sodium starch glycolate; effervescing mixtures;dyestuff; sweeteners; wetting agents such as lecithin, polysorbates orlaurylsulfates; and other therapeutically acceptable accessoryingredients, such as humectants, preservatives, buffers andantioxidants, which are known additives for such formulations.

For oral administration, fine powders or granules containing diluting,dispersing and/or surface-active agents may be presented in a draught,in water or a syrup, in capsules or sachets in the dry state, in anon-aqueous suspension wherein suspending agents may be included, or ina suspension in water or a syrup. Where desirable, flavoring,preserving, suspending, thickening or emulsifying agents can beincluded.

Liquid dispersions for oral administration may be syrups, emulsions orsuspensions. The syrups may contain as carrier, for example, saccharoseor saccharose with glycerol and/or mannitol and/or sorbitol. Inparticular, a syrup for diabetic patients can contain as carriers onlyproducts, for example sorbitol, which do not metabolize to glucose orwhich metabolize only a very small amount to glucose. The suspensionsand the emulsions may contain a carrier, for example a natural gum,agar, sodium alginate, pectin, methylcellulose, carboxymethylcelluloseor polyvinyl alcohol. The ingredients mentioned herein are not intendedto be exhaustive, and one of skill in the art will be able to formulatecompositions using known or to be known ingredients.

It is contemplated that the dextrorphan conjugates of the presenttechnology can be combined with one or more active substances, such asdifferent dextrorphan conjugates, unconjugated dextrorphan, or otheractive ingredient(s) depending on intended indication. Examples ofactive pharmaceuticals that can be combined with the conjugates of thepresent technology include, but are not limited to, acetaminophen,phenylpropanolamine, ibuprofen, aspirin, diflusinal, salicylic acid,dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen,flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac,etodolac, ketorolac, diclofenac, piroxicam, meloxicam, tenoxicam,lornoxicam, isoxicam, mefenamic acid, meclofenamic acid, flufenamicacid, tolfenamic acid, celecoxib, valdecoxib, lumiracoxib, pheniramine,chlorpheniramine, fexofenadine, azelastine, hydroxyzine,diphenhydramine, desloratidine, loratidine, cyproheptadine,bromopheniramine, emedastine, levocabastine, carbinoxamine,levocetirizine, clemastine, cetirizine, phenylephrine, pseudoephedrine,oxymetazoline, pyrilamine, doxylamine, codeine, pholcodine,dextromethorphan, noscapine, butamirate, acetylcysteine, menthol,quetiapine, and guaifenesin. The conjugated dextrorphan of the presenttechnology can be formulated with one or a combination of these or otheractive substances, or as a stand alone active ingredient without anyother actives.

The amounts and relative percentages of the different active andinactive components of the formulations of the current technology can bemodified, selected and adjusted in order to arrive at desirableformulations, dosages and dosage forms for therapeutic administration ofthe compounds, products, compositions, conjugates and prodrugs of thecurrent technology.

In one embodiment, the compositions comprising the dextrorphanconjugates or prodrugs may be used in methods of treating a patienthaving a disease, disorder, condition, or syndrome requiring or mediatedby binding of an NMDA receptor antagonist to an NMDA receptor of thepatient. In some embodiments, compositions comprising the dextrorphanconjugates of the present technology may be used as an anesthetic, orfor the treatment of such conditions as opioid dependence, hyperalgesia,pseudobulbar affect (PBA), neuropathy, diabetic peripheral neuropathicpain, catalepsy, amnesia, Alzheimer's disease, depression, andpost-traumatic stress disorder (PTSD). In certain embodiments, thecompositions comprising the dextrorphan conjugates of the presenttechnology may be used in combination with quinidine for the treatmentof PBA and/or PTSD. In other embodiments, compositions of the presenttechnology may potentiate the effects of certain opioids, such as forexample oxycodone, in suppressing neuropathic pain, thus potentiallypermitting a lower dose of oxycodone to be administered to a patient andthereby decreasing side effects of oxycodone treatment of neuropathicpain in said patient.

Treatment comprises orally administering to the patient apharmaceutically effective amount of at least one conjugate ofdextrorphan as described in the present technology. The patient may be ahuman or animal patient. As used herein, the term animal is used in theveterinary sense and does not include humans. Human patients who may betreated include neonatal patients, pediatric patients, adolescentpatients, adult patients, geriatric patients, elderly patients, andnormative patients. In some embodiments, the conjugate can exhibit alower, equivalent, or higher AUC when compared to an equivalent molaramount of unconjugated dextrorphan, and can exhibit a slower, similar,or faster rate of release. In other embodiments, at least one conjugatecan exhibit less variability in the oral PK profile when compared tounconjugated dextrorphan.

In some embodiments, the prodrugs or compositions of the presenttechnology may be administered for the relief or suppression of cough,impulse to cough, sneezing, itching of the nose, throat or watery eyes,nasal congestion, sinus congestion and pressure, sore throat, headache,minor aches and pains, muscular pain, fever, upper respiratory symptoms,and bronchial irritation. Dosing of the prodrugs or compositions will bedependent on the age and body weight of the patient, and the severity ofthe symptoms to be treated.

In some embodiments, dosages of the dextrorphan conjugate of the presenttechnology include, but are not limited to, formulations including fromabout 0.5 mg or higher, alternatively from about 2.5 mg or higher,alternatively from about 5.0 mg or higher, alternatively from about 7.5mg or higher, alternatively from about 10 mg or higher, alternativelyfrom about 20 mg or higher, alternatively from about 30 mg or higher,alternatively from about 40 mg or higher, alternatively from about 50 mgor higher, alternatively from about 60 mg or higher, alternatively fromabout 70 mg or higher, alternatively from about 80 mg or higher,alternatively from about 90 mg or higher, alternatively from about 100mg or higher of the dextrorphan conjugate, and include any additionalincrements thereof, for example, 0.1, 0.2, 0.25, 0.3, 0.4, 0.5, 0.6,0.7, 0.75, 0.8, 0.9 or 1.0 mg and multiplied factors thereof, (e.g., ×1,×2, ×2.5, ×5, ×10, ×100, etc.).

In some embodiments, compositions comprising the dextrorphan conjugatesof the present technology could be orally administered at a dosingregimen of one time a day, alternatively two times a day, alternativelyfour times a day. In some embodiments, doses of the compositioncomprising the levorphanol conjugate could be administered at 1 doseevery 4 to 6 hours, alternatively 1 to 2 doses every 4 to 6 hours,alternatively every 6 to 8 hours, alternatively 4 doses in a 24 hourperiod. In further embodiments, doses of the composition comprising thelevorphanol conjugate could be administered at 1 dose about every 12hours, alternatively 1 to 2 doses about every 12 hours, alternatively 2doses every 24 hours, alternatively 1 dose about every 24 hours.

In some embodiments, compositions comprising the dextrorphan conjugatesof the present technology could be administered for a period of about 3days, alternatively about 5 days, alternatively about 7 days,alternatively about 10 days, alternatively about 12 days, alternativelyabout 14 days, alternatively about 21 days, alternatively about 30 days,alternatively about 60 days, alternatively about 90 days, alternativelyabout 120 days, alternatively more than 120 days.

Pharmaceutical Kits

In some embodiments, the present technology provides pharmaceutical kitscomprising a dextrorphan prodrug or composition of the presenttechnology. In some embodiments, a specific amount of individual dosesin a package contain a pharmaceutically and/or therapeutically effectiveamount of the dextrorphan prodrug or conjugate of the presenttechnology. In some embodiments, the kit comprises one or more blisterpacks containing the prodrug or composition of the present technology.In some embodiments, the kit may comprise one or more dextrorphanconjugate composition of the present technology and optionally one ormore additional compositions containing other active ingredients for aparticular treatment regimen. For example, the kit may be adaytime/nighttime kit that contains one composition for daytimetreatment and one composition for nighttime treatment. In otherembodiments, the kit could be, for example, a “family kit” thatcomprises different dosage strengths of the dextrorphan conjugatecomposition or different containers containing doses of the dextrorphanconjugate composition, for example, one dosage strength or container foradults, and another for children.

The kit can further include instructions for use of the kit. In someembodiments, the instructions for use are for the treatment of pain orcough in a neonatal, pediatric, adolescent, adult, normative, orgeriatric patient. In other embodiments, the instructions for use arefor the treatment of any of the diseases, disorders, conditions, orsyndromes identified above. The specified amount of individual doses maycontain from about 1 to about 100 individual dosages, alternatively fromabout 1 to about 60 individual dosages, alternatively from about 10 toabout 30 individual dosages, including, about 1, about 2, about 5, about10, about 15, about 20, about 25, about 30, about 35, about 40, about45, about 50, about 55, about 60, about 70, about 80, about 100, andinclude any additional increments thereof, for example, about 1, about2, about 5, about 10 and multiplied factors thereof, (e.g., about ×1,about ×2, about ×2.5, about ×5, about ×10, about ×100, etc.).

Synthetic Schemes

The present technology also provides a method of synthesis for thepreparation of the conjugated dextrorphan of the present technology. Insome embodiments, one or more protecting groups may be attached to anyadditional reactive functional groups that may interfere with thecoupling to dextrorphan. Any suitable protecting group may be useddepending on the type of functional group and reaction conditions. Someprotecting group suitable for use in the present technology include, butare not limited to, acetyl (Ac), tert-butyoxycarbonyl (Boc),benzyloxycarbonyl (Cbz), p-methoxybenzylcarbonyl (Moz),9-fluorenylmethyloxycarbonyl (Fmoc), benzyl (Bn), p-methoxybenzyl (PMB),3,4 dimethoxybenzyl (DMPM), p-methozyphenyl (PMP), tosyl (Ts), or amides(like acetamides, pthalamides, and the like).

In other embodiments, a base may be required at any step in thesynthetic scheme of prodrugs of dextrorphan of this invention. Suitablebases include, but are not limited to, 4-methylmorpholine (NMM),4-(dimethylamino)pyridine (DMAP), N,N-diisopropylethylamine, lithiumbis(trimethylsilyl)amide, lithium diisopropylamide (LDA), any alkalimetal tert.-butoxide (e.g., potassium tert.-butoxide), any alkali metalhydride (e.g., sodium hydride), any alkali metal alkoxide (e.g., sodiummethoxide), triethylamine or any other tertiary amine.

Suitable solvents that can be used for any reaction at any step in thesynthetic scheme of a prodrug of dextrorphan of this invention include,but are not limited to, acetone, acetonitrile, butanol, chloroform,dichloromethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO),dioxane, ethanol, ethyl acetate, diethyl ether, heptane, hexane,methanol, methyl tert.-butyl ether (MTBE), isopropanol, isopropylacetate, diisopropyl ether, tetrahydrofuran, toluene, xylene or water.

In some embodiments, an acid may be used to remove certain protectinggroups. Suitable acids include, but are not limited to, hydrochloricacid, hydrobromic acid, hydrofluoric acid, hydriodic acid, sulfuricacid, phosphoric acid, trifluoroacetic acid, acetic acid, citric acid,methanesulfonic acid, p-toluenesulfonic acid and nitric acid. Forcertain other protecting groups, a catalytic hydrogenation may be used,e.g., palladium on charcoal in the presence of hydrogen gas.

Provided herein are some reaction schemes that could be used to preparesome embodiments of the dextrorphan conjugates of the presenttechnology. It should be understood that the general reaction schemesprovided are exemplary, and that one skilled in the art can modify ortailor the reaction schemes to achieve particular outcomes, purposes,and/or advantages.

3-Val-dextrorphan 6

To a solution of dextrorphan, BocValOH and trimethylamine in DMF isadded a solution of HBTU in DMF. The reaction mixture is stirred at roomtemperature overnight. The reaction is quenched with water and thesolvent is evaporated under reduced pressure. The residue is taken inEtOAc, washed with 5% aq. NaHCO₃ and brine. The organic part is driedover anhydrous Na₂SO₄ and is evaporated to dryness to give3-(Boc-Val)-dextrorphan 3.

A solution of 3-(Boc-Val)-dextrorphan 3 in 4N HCl in dioxane is stirredat room temperature. The solvent is evaporated under reduced pressure,the residue is co-evaporated with IPAc and dried to give compound 6.

3-Phe-dextrorphan 7

A solution of HBTU is added to a solution of dextrorphan, Boc-Phe-OH,HOBt and trimethylamine in DMF is added. The reaction mixture is stirredat room temperature. The reaction is quenched with water and the solventis evaporated under reduced pressure. The residue is taken in EtOAc, andwashed with 5% aq. NaHCO₃ and brine. The organic part is dried overanhydrous Na₂SO₄ and is evaporated to dryness to give3-(Boc-Phe)-dextrorphan 4.

A solution of 3-(Boc-Phe)-dextrorphan 4 in 4N HCl in dioxane is stirredat room temperature. The solvent is evaporated under reduced pressure,the residue is co-evaporated with IPAc and is dried to give the compound7.

3-Ala-dextrorphan 8

Reaction of 1 and Boc-Ala-OH is performed following the same procedureas described for the synthesis of compound 7 to produce compound 5.Deprotection of 5 with 4N HCl in dioxane gives compound 8.

3-(AlaAlaVal)-dextrorphan 15

To a solution of 3-Val-dextrorphan 6 in DMF is added N-methylmorpholineand Boc-Ala-Ala-OSu. The reaction mixture is stirred at roomtemperature. The reaction is quenched with water and the solvent isevaporated under reduced pressure. The residue is partitioned betweenEtOAc and 5% aqueous NaHCO₃. The EtOAc layer is washed with 5% aq.NaHCO₃, brine, dried over anhydrous Na₂SO₄ and is evaporated to drynessto give 3-(Boc-AlaAlaVal)-dextrorphan 10.

The tripeptide derivative 10 is dissolved in 4N HCl in dioxane and isstirred at room temperature. Solvent is evaporated, the residue isco-evaporated with IPAc and is dried to give the tripeptide derivative15.

3-(ValValPhe)-dextrorphan 16

To a solution of 3-Phe-dextrorphan 7 and N-methylmorpholine in DMF isadded Boc-ValVal-OSu. The reaction mixture is stirred at roomtemperature and is then heated. The reaction is quenched with water andthe solvent is evaporated under reduced pressure and gives3-(Boc-ValValPhe)-dextrorphan 11.

A solution of compound 11 in 4N HCl in dioxane is stirred at roomtemperature. Solvent is evaporated, the residue is co-evaporated withIPAc and is dried to give the tripeptide derivative 16.

3-(PhePhePhe)-dextrorphan 17

To a solution of 3-Phe-dextrorphan 7 in DMF is added N-methylmorpholineand Boc-PhePhe-OSu. The reaction mixture is stirred at room temperature.The reaction is quenched with water and the solvent is evaporated underreduced pressure. The residue is taken in EtOAc, and washed with 5%aqueous NaHCO₃ and brine. The organic part is dried over anhydrousNa₂SO₄ and is evaporated to dryness to give3-(Boc-PhePhePhe)-dextrorphan 12.

Compound 12 is dissolved in 4N HCl in dioxane and is stirred at roomtemperature. Solvent is evaporated, the residue is co-evaporated withIPAc and is dried to give the tripeptide derivative 17.

3-(ProProPhe)-dextrorphan 18

Compound 18 is prepared following the procedure described for thesynthesis of compound 16, except Boc-ProPro-OSu is used in place ofBoc-ValVal-OSu.

3-(GlyGlyAla)-dextrorphan 19

A mixture of compound 8, N-methylmorpholine and Boc-GlyGly-OSu in DMF isstirred at room temperature. Solvent is evaporated under reducedpressure to give the tripeptide derivative 14.

A solution of 14 in 4N HCl in dioxane is stirred at room temperature.Solvent is removed under vacuum, the residue is co-evaporated with IPAcand is dried to give 19.

3-(N-succinoyl-Val)-dextrorphan 20

A solution of compound 6, triethylamine and succinic anhydride in DMF isheated. Solvent is evaporated under reduced pressure and provides3-(N-succinoyl-Val)-dextrorphan. The purified product is treated with 4NHCl in dioxane to give the hydrochloride salt 20.

3-Hippuryl-dextrorphan 22

To a solution of dextrorphan 1, hippuric acid, HOBt and trimethylaminein DMF is added a solution of HBTU in DMF. The reaction mixture isstirred at room temperature. The reaction is quenched with water and thesolvent is evaporated under reduced pressure. The residue is taken inEtOAc, and washed with 5% aq. NaHCO₃ and brine. The EtOAc part is driedover anhydrous Na₂SO₄ and is evaporated to dryness to give3-hippuryl-dextrorphan. The purified product is dissolved in 4N HCl indioxane and is stirred at room temperature. The solvent is evaporatedunder reduced pressure, and the residue is co-evaporated with IPAc andis dried to obtain hydrochloride salt 22.

3-(N-acetyl-Ile)-dextrorphan 23

Reaction of dextrorphan with Ac-Ile-OH is carried out in a mannersimilar to that described for the synthesis of 22 to obtain3-(N-acetyl-Ile)-dextrorphan. The N-acetyl-isoleucine derivative isconverted to the corresponding hydrochloride salt by treatment with 4NHCl in dioxane to give the hydrochloride salt 23.

3-(N-acetyl-Tyr)-dextrorphan 25

Reaction of dextrorphan, Ac-Tyr(^(t)Bu)-OH to give compound 24 iscarried out following the same procedure as described for the synthesisof 22.

A solution of 24 in 4N HCl in dioxane is stirred at room temperature.Solvent is evaporated and the residue is co-evaporated with IPAc and isdried to give compound 25.

3-(Acetyl-OCH(phenyl)C(O))-dextrorphan 26

The reaction of dextrorphan and O-acetylmandelic acid is carried outfollowing the same procedure as described for the synthesis of 22. Thecrude product is purified and is then converted to the HCl salt bytreatment with 2N HCl in dioxane to produce hydrochloride salt 26.

3-Cinnamoyl-dextrorphan 28

A solution of cinnamoyl chloride in CH₂Cl₂ is added to a solution ofdextrorphan 1 and trimethylamine in CH₂Cl₂. After the addition, thereaction mixture is stirred. Additional CH₂Cl₂ is added and the organicpart is washed with 5% aqueous NaHCO₃, and brine. The CH₂Cl₂ part isdried over anhydrous Na₂SO₄ and is evaporated to dryness to afford3-cinnamoyl-dextrorphan. The purified product is dissolved in 4N HCl indioxane and is stirred at room temperature. Solvent is evaporated undervacuum and the residue is dried to give hydrochloride salt of 28.

3-(Acetyl-OCH₂C(O))-dextrorphan 29

A solution of dextrorphan 1 and trimethylamine in CH₂Cl₂ is cooled and asolution of acetyloxyacetyl chloride in CH₂Cl₂ is added drop wise. Afterthe addition, the reaction mixture is stirred at room temperature. Thereaction is quenched with water and the solvent is evaporated underreduced pressure. The product is purified and is treated with 2N HCl indioxane to give hydrochloride salt 29.

3-(Acetyl-OCH(CH₃)C(O))-dextrorphan 30

A solution O-acetyl lactyl chloride in CH₂Cl₂ is added to a solution ofdextrorphan 1 and trimethylamine in CH₂Cl₂. After the addition, thereaction mixture is stirred. Solvent is evaporated under reducedpressure. The residue is dissolved in CH₂Cl₂, and washed with 5% aqueousNaHCO₃ and brine. The CH₂Cl₂ part is dried over anhydrous Na₂SO₄ and isevaporated to dryness. The crude product is purified and is converted tothe corresponding hydrochloride salt 30 by treatment with 2N HCl indioxane.

3-(Chloromethyloxycarbonyl)-dextrorphan 32

A solution of chloromethyl chloroformate 31 in CH₂Cl₂ is added to asolution of dextrorphan and trimethylamine in CH₂Cl₂. After theaddition, the reaction mixture is stirred. The reaction is quenched withwater and solvent is evaporated under reduced pressure. The residue istaken in EtOAc, and washed with water and brine, is dried over anhydrousNa₂SO₄ and is evaporated to dryness to give 32.

3-(Benzoyl-OCH₂OC(O)-dextrorphan 34

A solution of 32 and sodium benzoate in DMF is heated. Solvent isevaporated under reduced pressure. The residue is taken in EtOAc, andwashed with 5% aq. NaHCO₃ and brine. The organic part is dried overanhydrous Na₂SO₄ and is evaporated to dryness to give 34. The purifiedbenzoyl derivative is dissolved in 4N HCl in dioxane, is stirred at roomtemperature, and then solvent is evaporated under vacuum. The resultingresidue is dried to give the hydrochloride salt of 34.

3-(Butanoyl-OCH₂OC(O))-dextrorphan 35

Reaction of 32 with sodium butyrate to obtain 35 is carried out in amanner similar to that described for the synthesis of 34. The crudeproduct is purified and is treated with 4N HCl in dioxane to obtainhydrochloride salt of 35.

3-(Cinnamoyl-OCH₂OC(O))-dextrorphan 36

A solution of 32 and sodium cinnamate in DMF is heated. Solvent isevaporated under reduced pressure. The residue is taken in EtOAc, andwashed with 5% aq. NaHCO₃ and brine. The organic part is dried overanhydrous Na₂SO₄ and is evaporated to dryness. The crude product isisolated as hydrochloride salt of 36 by treatment with 4N HCl indioxane.

3-(N,O-acetyl-Lys-OCH₂OC(O))-dextrorphan 37

A solution of 32 and Ac-Lys(Ac)-ONa in DMF is heated. Solvent isevaporated under reduced pressure. The residue is taken in EtOAc, andwashed with 5% aq. NaHCO₃ and brine. The organic part is dried overanhydrous Na₂SO₄ and is evaporated to dryness. The crude product ispurified and is treated with 4N HCl in dioxane to give hydrochloridesalt of 37.

General Procedure for the Synthesis of Sodium Salt of N-Protected AminoAcids (Boc-AA-ONa)

To a solution or suspension or solution (depending on amino acids) ofBoc-AA-OH in CH₃CN/water is added 1N NaOH drop-wise while stirring.

3-(Boc-Val-OCH₂OC(O))-dextrorphan 38

A solution of 32 and Boc-Val-ONa in DMF is heated. Solvent is evaporatedunder reduced pressure. The residue is taken in EtOAc, and washed with5% aq. NaHCO₃ and brine. The organic part is dried over anhydrous Na₂SO₄and is evaporated to dryness to give 38.

3-(Val-OCH₂OC(O))-dextrorphan 40

A solution of 38 in 4N HCl in dioxane is stirred at room temperature.Solvent is evaporated under reduced pressure, the residue isco-evaporated with IPAc and is dried to give 40. Compound 40 isconverted to the acetyl derivative 42.

3-(N-acetyl-Val-OCH₂OC(O))-dextrorphan 42

A solution of 40 and TEA in CH₂Cl₂ is cooled and a solution of acetylchloride in CH₂Cl₂ is added drop wise. The reaction mixture is stirredat room temperature. Solvent is evaporated under reduced pressure andthe residue is partitioned between EtOAc and 5% aqueous NaHCO₃. TheEtOAc layer is washed with 5% aq. NaHCO₃ and brine, is dried overanhydrous Na₂SO₄ and is evaporated to dryness.

The purified product is dissolved in 4N HCl in dioxane, is stirred andis then evaporated to dryness under vacuum to give the hydrochloridesalt 42.

3-(N,O-diacetyl-Tyr)-dextrorphan 43

A solution of 32 and Boc-Tyr(^(t)Bu)-ONa in DMF is stirred at roomtemperature, and then is heated. Solvent is evaporated under reducedpressure. The residue is dissolved in EtOAc, and washed with 5% aq.NaHCO₃ and brine. The organic part is dried over anhydrous Na₂SO₄ and isevaporated to dryness to give 39.

Compound 39 is dissolved in 4N HCl in dioxane and the solution isstirred at room temperature. Solvent is evaporated under reducedpressure, and the residue is co-evaporated with IPAc and is dried togive 41.

A solution of 41 and TEA in CH₂Cl₂ is cooled and a solution of acetylchloride in CH₂Cl₂ is added drop wise. After the addition, the reactionmixture is stirred at room temperature. Solvent is evaporated underreduced pressure and the residue is partitioned between EtOAc and 5%aqueous NaHCO₃. The EtOAc layer is washed with 5% aq. NaHCO₃ and brine,is dried over anhydrous Na₂SO₄ and is evaporated to dryness. The crudeproduct is purified and is then treated with 4N HCl in dioxane to givethe hydrochloride salt 43.

3-Biotinyl-dextrorphan 45

A solution of HBTU in DMF is added to a solution of dextrorphan 1,biotin 44, HOBt and trimethylamine in DMF at room temperature. Thereaction is quenched with water and the solvent is evaporated underreduced pressure. 5% Aqueous NaHCO₃ is added to the residue and themixture is extracted with CH₂Cl₂. The combined organic parts is washedwith 5% aq. NaHCO₃ and brine, is dried over anhydrous Na₂SO₄ and isevaporated to dryness to give 3-biotinyl-dextrorphan. The crude productis purified and is treated with 4N HCl in dioxane to give thehydrochloride salt 45.

3-(Methoxy-(ethoxy)-CH₂C(O))-dextrorphan 48

A solution of 2-methoxyethoxy acetyl chloride 46 in CH₂Cl₂ is added to asolution of dextrorphan and trimethylamine in CH₂Cl₂. After theaddition, the reaction mixture is stirred. Additional CH₂Cl₂ is added,and the organic part is washed with 5% aqueous NaHCO₃ and brine. TheCH₂Cl₂ part is dried over anhydrous Na₂SO₄ and is evaporated to dryness.The residue is purified, is dissolved in 4N HCl in dioxane, is stirredat room temperature, and is then evaporated under reduced pressure togive the hydrochloride salt 48.

3-(Methoxy-PEG₂-CH₂C(O))-dextrorphan 49

To a solution of dextrorphan 1, 2-[2-2-methoxyethoxy)ethoxy] acetic acid47, HOBt and trimethylamine in DMF is added a solution of HBTU in DMF.The reaction mixture is stirred at room temperature. The reaction isquenched with water and the solvent is evaporated under reducedpressure. The residue is partitioned between CH₂Cl₂ and 5% aq. NaHCO₃.The aqueous part is extracted with CH₂Cl₂. The combined organic part isfinished with brine, is dried over anhydrous Na₂SO₄ and is evaporated todryness. The purified product is dissolved in 2N HCl in dioxane, isstirred at room temperature and is then evaporated under reducedpressure to give the hydrochloride salt 49.

3-(H₂N-PEG₄-CH₂CH₂C(O))-dextrorphan 54

To a solution of dextrorphan 1, Boc-NH-(PEG)₄-CH₂CH₂—COOH 50, HOBt andtrimethylamine in DMF is added a solution of HBTU in DMF. The reactionmixture is stirred at room temperature. The reaction is quenched withwater and the solvent is evaporated under reduced pressure. The residueis taken in EtOAc, and washed with 5% aq. NaHCO₃ and brine. The organicpart is dried over anhydrous Na₂SO₄ and is evaporated to dryness to give53.

A solution of 53 in 4N HCl in dioxane is stirred at room temperature.Solvent is evaporated under pressure, the residue is co-evaporated withIPAc and is dried to give the deprotected product 43.

3-(N₃-PEG₄-CH₂CH₂C(O))-dextrorphan 55

A solution of HBTU in DMF is added to a solution of dextrorphan 1,N₃-(PEG)₄-CH₂CH₂—COOH 51, HOBt and trimethylamine in DMF. The reactionmixture is stirred at room temperature. The reaction is quenched withwater and the solvent is evaporated under reduced pressure. The residueis taken in CH₂Cl₂, and washed with 5% aq. NaHCO₃ and brine. The organicpart is dried over anhydrous Na₂SO₄ and is evaporated to dryness. Thepurified product is dissolved in 2N HCl in dioxane and is stirred atroom temperature. Solvent is evaporated under pressure, is co-evaporatedwith IPAc and is dried to give the hydrochloride salt 55.

3-(H₂N-PEG₆-CH₂CH₂C(O))-dextrorphan 57

To a solution of dextrorphan 1, Boc-NH-(PEG)₆-CH₂CH₂—COOH, HOBt andtrimethylamine in DMF is added a solution of HBTU in DMF. The reactionmixture is stirred at room temperature. The reaction is quenched withwater and the solvent is evaporated under reduced pressure. The residueis taken in CH₂Cl₂, and washed with 5% aq. NaHCO₃ and brine. The organicpart is dried over anhydrous Na₂SO₄ and is evaporated to dryness to give56.

A solution of 56 in 4N HCl in dioxane is stirred at room temperature.Solvent is evaporated under pressure, the residue is co-evaporated withIPAc, and is dried to give the deprotected product 57.

3-Acetyl-N-(acetyl-OCH₂)-dextrorphanium 3

A solution of dextrorphan 1, 1,2,2,6,6-pentamethylpiperidine andacetyloxymethyl bromide 58 in CH₃CN is heated. Solvent is evaporatedunder reduced pressure. The purified quaternary salt is dissolved in 4NHCl in dioxane and is stirred at room temperature. The solvent isevaporated, the residue is co-evaporated with IPAc and is dried to givethe chloride salt 59.

N-(Acetyl-OCH₂)-dextrorphanium 60

A solution of dextrorphan 1 and acetyloxymethyl bromide 58 in CH₃CN isheated. Solvent is evaporated under reduced pressure. The purifiedquaternary salt is dissolved in 4N HCl in dioxane and is stirred at roomtemperature. The solvent is evaporated, the residue is co-evaporatedwith IPAc and is dried to give the chloride salt 60.

N-(Pivaloyl-OCH₂)-dextrorphanium 62,3-pivaloyl-N-(pivaloyl-OCH₂)-dextrorphanium Chloride 63 and3-pivaloyl-dextrorphan 64

A suspension of dextrorphan 1 and chloromethyl pivalate 61 in CH₃CN isheated. Solvent is evaporated under reduced pressure. The quaternarysalts, after separation, is treated with Dowex 1×4 chloride form, isfiltered and the filtrate is lyophilized to afford compound 62 and 63.In addition, conjugate 64 may form.

Prophetic Synthesis of Cbz-Val-O—CH₂—Cl

Prophetic Synthesis of N-(Val-CH₂)-dextrorphanium

Prophetic Synthesis of MeO-PEG₃-CH₂C(O)OCH₂—Cl

Prophetic Synthesis of N-(MeO-PEG₃-CH₂C(O)OCH₂)-dextrorphanium

Prophetic Synthesis of Boc-Ser(C(O)OCH₂Cl)—O^(t)Bu

Prophetic Synthesis of N-(Ser(C(O)OCH₂)—OH)-dextrorphanium

N-(pivaloyl-OCH₂)-dextrorphanium Chloride 62,3-pivaloyl-N-(pivaloyl-OCH₂)-dextrorphanium Chloride 63 and3-pivaloyl-dextrorphan 64

A suspension of dextrorphan 1 and chloromethyl pivalate 61 in CH₃CN isheated. Solvent is evaporated under reduced pressure. The quaternarysalts, after separation, is treated with Dowex 1×4 chloride form, isfiltered and the filtrate is lyophilized to afford compound 62 and 63.In addition, 3-monosubstituted dextrorphan conjugate 64 may form.

3-pivaloyl-N-(pivaloyl-OCH₂)-dextrorphanium Chloride 63 and3-pivaloyl-dextrorphan 64

In an alternative reaction scheme, a mixture of dextrorphan 1,1,2,2,6,6-pentamethyl piperidine and chloromethyl pivalate 61 in CH₃CNis heated. Solvent is evaporated under reduced pressure. The quaternarysalt is treated with Dowex 1×4 chloride form and is lyophilized to givecompound 63. In addition, 3-monosubstituted dextrorphan conjugate 64 mayform.

3-(Ethoxy-C(O))—N-(ethoxy-C(O)CH(CH₃))-dextrorphanium chloride 66 and3-(ethoxy-C(O))-dextrorphan 67

A mixture of dextrorphan 1, 1-chloroethyl ethyl carbonate 65,1,2,2,6,6-pentamethylpiperidine and NaI in CH₃CN is heated. Solvent isevaporated under reduced pressure. The quaternary salt is treated withDowex 1×4 chloride form, is filtered and the filtrate is lyophilized togive compound 66. In addition, 3-monosubstituted dextrorphan conjugate67 may form.

Prophetic Synthesis of Boc-Phe-CH(Me)-COOH

Prophetic Synthesis of Nicotinoyl-O—CH₂—Cl

Prophetic Synthesis of3-(Phe-CH(Me)C(O))—N-(nicotinoyl-OCH₂)-dextrorphanium

The presently described technology and its advantages will be betterunderstood by reference to the following examples. These examples areprovided to describe specific embodiments of the present technology. Byproviding these specific examples, it is not intended limit the scopeand spirit of the present technology. It will be understood by thoseskilled in the art that the full scope of the presently describedtechnology encompasses the subject matter defined by the claimsappending this specification, and any alterations, modifications, orequivalents of those claims.

EXAMPLES Example 1: Synthesis of 3-Val-dextrorphan 6

To a solution of dextrorphan 1 (0.13 g, 0.505 mmol), Boc-Val-OH (0.12 g,0.55 mmol), HOBt (0.072 g, 0.53 mmol) and trimethylamine (0.175 mL, 1.26mmol) in DMF (7 mL) was added a solution of BOP (0.235 g, 0.53 mmol) inDMF (3 mL) at 0° C. After the addition, the reaction mixture was stirredovernight at room temperature. The reaction was quenched with water (1mL) and the solvent was evaporated under reduced pressure. The residuewas taken in EtOAc (100 mL), washed with 5% aq. NaHCO₃ (1×70 mL), 10%aq. NH₄Cl (1×60 mL) and brine (1×60 mL). The organic layer was driedover anhydrous Na₂SO₄ and evaporated to dryness. The solid residue waspurified by preparative HPLC to give 3-(Boc-Val)-dextrorphan 3.

3-(Boc-Val)-dextrorphan 3 was dissolved in dioxane (3 mL) and to thesolution was added 4N HCl in dioxane (9 mL). The reaction mixture wasstirred at room temperature for 3 hours. The solvent was evaporatedunder reduced pressure, the residue was co-evaporated with IPAc anddried to give 3-Val-dextrorphan 6 as a white to off-white solid in 75%yield (from dextrorphan).

Example 2: Synthesis of 3-(N-acetyl-Val)-dextrorphan 68

A solution of 3-Val-dextrorphan 6 (0.095 g, 0.22 mmol) and TEA (0.18 mL,1.32 mmol) in CH₂Cl₂ (5 mL) was cooled down to 0-5° C. and a solution ofacetyl chloride (0.062 mL, 0.88 mmol) in CH₂Cl₂ (1 mL) was addeddropwise. After the addition of acetyl chloride, the reaction mixturewas stirred at 0° C. for 1.5 hours. Solvent was evaporated under reducedpressure and the residue was purified by preparative HPLC to give3-(N-acetyl-Val)-dextrorphan.

To a solution of 3-(N-acetyl-Val)-dextrorphan in dioxane (2 mL) wasadded 4N HCl in dioxane (2 mL). The solution was stirred at roomtemperature for 10 minutes and then evaporated to dryness under vacuumto give the hydrochloride salt 68 as waxy solid (0.054 g, 56% yield)

Example 3: Synthesis of 3-(N-acetyl-Val-OCH₂OC(O))-dextrorphan 41

3-(Boc-Val-OCH₂OC(O))-dextrorphan 38

A solution of chloromethyl chloroformate 31 (0.135 mL, 1.5 mmol) inCH₂Cl₂ (2 mL) was added to a solution of dextrorphan 1 (0.258 g, 1 mmol)and trimethylamine (0.42 mL, 3 mmol) in CH₂Cl₂ (8 mL) at 0-5° C. Afterthe addition, the reaction mixture was stirred for 1 hour at 0-5° C. Thereaction was quenched with water and solvents were evaporated underreduced pressure. The residue was taken in EtOAc (100 mL), washed with5% aq. NaHCO₃ (1×70 mL), brine (1×70 mL), dried over anhydrous Na₂SO₄and evaporated to dryness to give3-(chloromethyloxycarbonyl)-dextrorphan 32. The crude product was usedin the next reaction without further purification.

A solution of 3-(chloromethyloxycarbonyl)-dextrorphan 32 (0.35 g, 1mmol) and Boc-Val-ONa (0.36 g, 1.5 mmol) in DMF (10 mL) was heated for 2hours at 60° C. Solvent was evaporated under reduced pressure. Theresidue was taken in EtOAc (110 mL), washed with 5% aq. NaHCO₃ (2×75 mL)and brine (1×75 mL). The organic layer was dried over anhydrous Na₂SO₄and evaporated to dryness. The crude product was purified by preparativeHPLC to give 3-(Boc-Val-OCH₂OC(O))-dextrorphan 38 (0.23 g, 43%).

3-(N-acetyl-Val-OCH₂OC(O))-dextrorphan 41

To a solution of 3-(Boc-Val-OCH₂OC(O))-dextrorphan 38 (0.23 g) indioxane (2 mL) was added 4N HCl in dioxane (8 mL) and the solution wasstirred for 3 hours at room temperature. Solvent was evaporated underreduced pressure, the residue was co-evaporated with IPAc and dried togive 3-(Val-OCH₂OC(O))-dextrorphan 40 in quantitative yield.

A solution of acetyl chloride (0.085 mL, 1.2 mmol) in CH₂Cl₂ (1 mL) wasadded dropwise to a solution of 3-(Val-OCH₂OC(O))-dextrorphan 40 (0.15g, 0.3 mmol) and TEA (0.25 mL, 1.8 mmol) in CH₂Cl₂ (8 mL) at 0° C. Thereaction mixture was stirred for 2 hours at 0° C. Solvents wereevaporated under reduced pressure and the crude product was purified bypreparative HPLC to give 3-(N-acetyl-Val-OCH₂OC(O))-dextrorphan.

The purified product was dissolved in dioxane (1.5 mL) and to thesolution was added 4N HCl in dioxane (4.5 mL). The solution was stirredfor 10 minutes and evaporated to dryness under vacuum to give thehydrochloride salt 41. (0.08 g, 56%).

Example 4: Synthesis of 3-Acetyl-N-(acetyl-OCH₂)-dextrorphanium 59

A solution of dextrorphan 1 (0.08 g, 0.31 mmol),1,2,2,6,6-pentaethylpiperidine (0.14 mL, 0.77 mmol) and acetyloxymethylbromide 58 (0.076 mL, 0.77 mmol) in CH₃CN was heated for 1.5 hours at70° C. Solvents were evaporated under reduced pressure and the residuewas purified by preparative HPLC. The purified quaternary salt wasdissolved in 4N HCl in dioxane and stirred for 20 minutes at roomtemperature. The solvent was evaporated, the residue was co-evaporatedwith IPAc and dried to give the chloride salt 59 (0.095 g, 75%).

Example 5: Synthesis of N-(Acetyl-OCH₂)-dextrorphanium 60

A solution of dextrorphan 1 (0.077 g, 0.3 mmol) and acetyloxymethylbromide 58 (0.06 mL, 0.6 mmol) in CH₃CN (8 mL) was heated for 1 hour at70° C. The solution was cooled down to room temperature and solvent wasevaporated under reduced pressure. The crude product was purified bypreparative HPLC. The purified quaternary salt was dissolved in 4N HClin dioxane and stirred at room temperature for 20 minutes. The solventwas evaporated, the residue was co-evaporated with IPAc and dried togive the chloride salt 60 (0.065 g, 59%) as white solid.

Example 6: Comparison of Oral PK Profiles of Conjugates of Dextrorphanin Rats

Conjugates of dextrorphan and dextrorphan tartrate comparator compoundwere dissolved in an appropriate vehicle and administered in rats viaoral gavage. A summary of the doses and vehicles used for each compoundis provided in Table 1. Whole blood samples were collected viaretro-orbital bleeding at 0.25, 0.5, 1, 2, 3, and 4 hours postdose.Blood samples were centrifuged and the resulting plasma samples werecollected for analysis of dextrorphan concentrations by LC-MS/MS. PKprofiles comparing the plasma concentrations of dextrorphan releasedfrom the conjugates and from the dextrorphan tartrate comparator areshown in FIGS. 13-16.

Example 7: Comparison of Intranasal PK Profiles of Dextrorphan Conjugateand Unconjugated Dextrorphan in Rats

3-(N-acetyl-Val)-dextrorphan HCl conjugate and dextrorphan tartratecomparator compound were dissolved in an appropriate vehicle andadministered in rats by slowly adding the respective dosing solutiondrop-wise and alternating into the nasal openings. A summary of thedoses and vehicles used for each compound is provided in Table 1. Wholeblood samples were collected via retro-orbital bleeding at 5 minutes andat 0.25, 0.5, and 1 hours postdose. Blood samples were centrifuged andthe resulting plasma samples were collected for analysis of dextrorphanconcentrations by LC-MS/MS. PK profiles comparing the plasmaconcentrations of dextrorphan released from the conjugate and from thedextrorphan tartrate comparator are shown in FIG. 17.

TABLE 1 Conjugate Comparator^(a) Dose Dose Conjugate (mg/kg) (mg/kg)Vehicle^(b) ROA^(c) 3-(N-acetyl-Val)- 6.41 6.00 Water Oral dextrorphanHCl 3-(N-acetyl-Val- 7.50 6.00 Water Oral OCH₂OC(O))- dextrorphan HCl3-Val-dextrorphan 6.32 6.00 Water Oral 2HCl N-(acetyl-OCH₂)- 5.39 6.00Water Oral dextrorphanium Cl 3-acetyl-N-(acetyl- 6.01 6.00 Water OralOCH₂)- dextrorphanium Cl 3-(N-acetyl-Val)- 0.21 0.20 Water Intranasaldextrorphan HCl ^(a)comparator = dextrorphan tartrate; the comparatorand conjugate doses are equimolar ^(b)the same vehicle was used forconjugate and comparator ^(c)ROA = route of administration

In the present specification, use of the singular includes the pluralexcept where specifically indicated.

The compounds, compositions, prodrugs, and methods described herein canbe illustrated by the following embodiments enumerated in the numberedparagraphs that follow:

1. A compound or composition comprising at least one conjugate ofdextrorphan having the following general formula:

-   -   where L¹ is absent, or is

-   -   Y¹ is absent, or [A-X—Z]_(n)    -   where A, X, Z are independently absent or selected from —O—, —S—        or —(CR¹R²)_(k)—    -   R¹, R² are each independently selected from H, alkyl, aryl,        alkylaryl, alkoxy, haloalkyl, or haloaryl    -   n and k are independently 1-4    -   G_(m) ¹ is absent or selected independently for each repeating        subunit from H, oxoacid, polyethylene glycol having from 2 to 5        ethylene oxide units, or a vitamin compound, and m is 1-4,        except m is 1 when G¹ is H;    -   or a pharmaceutically acceptable salt thereof.

2. The compound or composition of paragraph 1, wherein L¹ and Y¹ areabsent, G¹ is at least one oxoacid, and m is 1-3.

3. The compound or composition of paragraph 1, wherein L¹ and Y¹ arepresent, G¹ is at least one oxoacid, and m is 1-3.

4. The compound or composition of paragraph 1, 2 or 3, wherein G¹ is atleast one oxoacid selected from the group consisting of aliphaticcarboxylic acid, aryl carboxylic acid, dicarboxylic acid, andpolycarboxylic acid.

5. The compound or composition of paragraph 1, 2 or 3, wherein G¹ is atleast one oxoacid selected from standard amino acids, non-standard aminoacids, synthetic amino acids, and combinations thereof.

6. The compound or composition of paragraph 1, 2 or 3, wherein G¹ is acombination of at least one oxoacid selected from the group consistingof aliphatic carboxylic acid, aryl carboxylic acid, dicarboxylic acid,and polycarboxylic acid and at least one oxoacid selected from standardamino acids, non-standard amino acids, synthetic amino acids, andcombinations thereof.

7. The compound or composition of paragraph 5 or 6, wherein the at leastone amino acid is a standard amino acid.

8. The compound or composition of paragraph 5 or 6, wherein the at leastone amino acid is a non-standard amino acid.

9. The compound or composition of paragraph 5 or 6, wherein the at leastone amino acid is a synthetic amino acid.

10. The compound or composition of paragraph 5 or 6, wherein the atleast one amino acid is valine.

11. The compound or composition of paragraph 4 or 6, wherein thecarboxylic acid is an aliphatic carboxylic acid selected from the groupconsisting of saturated carboxylic acids, monounsaturated carboxylicacids, polyunsaturated carboxylic acids, acetylenic carboxylic acids,substituted carboxylic acids, heteroatom containing carboxylic acids andring containing carboxylic acids.

12. The compound or composition of paragraph 11, wherein the saturatedcarboxylic acid is selected from the group consisting of methanoic,ethanoic, propanoic, butanoic, pentanoic, hexanoic, heptanoic, octanoic,2-propylpentanoic acid, pivalic acid, nonanoic, decanoic, dodecanoic,tetradecanoic, hexadecanoic, heptadecanoic, octadecanoic, and eicosanoicacid.

13. The compound or composition of paragraph 11, wherein themonounsaturated carboxylic acid is selected from the group consisting of4-decenoic, 9-decenoic, 5-lauroleic, 4-dodecenoic, 9-tetradecenoic,5-tetradecenoic, 4-tetradecenoic, 9-hexadecenoic, 6-hexadecenoic,6-octadecenoic, and 9-octadecenoic acid.

14. The compound or composition of paragraph 11, wherein thepolyunsaturated carboxylic acid is selected from the group consisting ofsorbic, octadecadienoic, octadecatrienoic, octadecatetraenoic,eicosatrienoic, eicosatetraenoic, eicosapentaenoic, docosapentaenoic,and docosahexaenoic acids.

15. The compound or composition of paragraph 11, wherein the acetyleniccarboxylic acid is selected from the group consisting of octadecynoic,octadecenynoic, 6,9-octadecenynoic, heptadecenynoic,tridecatetraenediynoic, tridecadienetriynoic, octadecadienediynoic,heptadecadienediynoic, octadecadienediynoic, octadecenediynoic, andoctadecenetriynoic acids.

16. The compound or composition of paragraph 11, wherein the substitutedcarboxylic acid is selected from the group consisting ofmethylpropanoic, isovaleric, methylhexadecanoic, 8-methyl-6-nonenoic,methyloctadecanoic, trimethyloctacosanoic, trimethyltetracosenoic,heptamethyltriacontanoic, tetramethylhexadecanoic,tetramethylpentadecanoic, lactic, glyceric, glycolic, threonic,3-hydroxypropionic, hydroxyoctadecatrienoic, hydroxyoctadecenoic,hydroxytetracosanoic, 2-hydroxybutyric, 3-hydroxybutyric,4-hydroxybutyric, 4-hydroxypentanoic, hydroxyoctadecadienediynoic,hydroxyoctadecadienoic, 10-hydroxydecanoic, hydroxydecenoic,hydroxyeicosenoic, hydroxyeicosadienoic, hydroxyhexadecanoic,dihydroxytetracosenoic, dihydroxydocosanoic, hydroxydocosanoic,trihydroxyoctadecanoic, trihydroxyhexadecanoic,trihydroxyicosahexaenoic, trihydroxyicosapentaenoic,2-methoxy-5-hexadecenoic, 2-methoxy hexadecanoic,7-methoxy-4-tetradecenoic, 9-methoxypentadecanoic,11-methoxyheptadecanoic, 3-methoxydocosanoic, diacetoxydocosanoic,2-acetoxydocosanoic, 2-acetoxytetracosanoic, 2-acetoxyhexacosanoic,9-oxononanoic, oxodecanoic, oxododecenoic, hydroxyoxodecenoic,10-oxo-8-decenoic, fluorooctadecenoic, fluorodecanoic,fluorotetradecanoic, fluorohexadecanoic, fluorooctadecadienoic,chlorohydroxyhexadecanoic, chlorohydroxyoctadecanoic,dichlorooctadecanoic, 3-bromo-2-nonaenoic, 9,10-dibromooctadecanoic,9,10,12,13-tetrabromooctadecanoic, 10-nitro-9,12-octadecadienoic,12-nitro-9,12-octadecadienoic, 9-nitro-9-octadecenoic, 9-oxo-2-decenoic,9-oxo-13-octadecenoic, oxooctadecatrienoic, 15-oxo-18-tetracosenoic,17-oxo-20-hexacosenoic, and 19-oxo-22-octacosenoic acids.

17. The compound or composition of paragraph 11, wherein the heteroatomcontaining carboxylic acid is selected from the group consisting of9-(1,3-nonadienoxy)-8-nonenoic, 9-(1,3,6-nonatrienoxy)-8-nonenoic,12-(1-hexenoxy)-9,11-dodecadienoic,12-(1,3-hexadienoxy)-9,11-dodecadienoic, 2-dodecylsulfanylacetic,2-tetradecylsulfanylacetic, 3-tetradecylsulfanylprop-2-enoic, and3-tetradecylsulfanylpropanoic acid.

18. The compound or composition of paragraph 11, wherein the ringcontaining carboxylic acid is selected from the group consisting of10-(2-Hexylcyclopropyl)decanoic,3-(2-[6-bromo-3,5-nondienylcyclopropyl)propanoic,9-(2-hexadecylcyclopropylidene)non-5-enoic,8-(2-octyl-1-cyclopropenyl)octanoic,7-(2-octyl-1-cyclopropenyl)heptanoic, 9,10-epoxyoctadecanoic,9,10-epoxy12-octadecenoic, 12,13-epoxy-9-octadecenoic,14,15-epoxy-11-eicosenoic, 11-(2-cyclopenten-1-yl)undecanoic,13-(2-cyclopenten-1-yl)tridecanoic, 13-(2-cyclopentenyl)-6-tridecenoic,11-cyclohexylundecanoic, 13-cyclohexyltridecanoic,7-(3,4-dimethyl-5-pentylfuran-2-yl)heptanoic,9-(4-methyl-5-pentylfuran-2-yl)nonanoic, 4-[5]-ladderane-butanoic,6-[5]-ladderane-hexanoic, and 6-[3]-ladderane-hexanoic acid.

19. The compound or composition of paragraph 4 or 6, wherein thecarboxylic acid is an aromatic carboxylic acid.

20. The compound or composition of paragraph 19 wherein the carboxylicacid is selected from the group consisting of benzoic acid,hydroxybenzoate, heteroaryl carboxylic acid, and combinations thereof.

21. The compound or composition of paragraph 20 wherein thehydroxybenzoate is selected from the group consisting of salicylic acid,acetylsalicylic acid (aspirin), 3-hydroxybenzoic acid, 4-hydroxybenzoicacid, 6-methylsalicylic acid, o,m,p-cresotinic acid, anacardic acids,4,5-dimethylsalicylic acid, o,m,p-thymotic acid, diflunisal,o,m,p-anisic acid, 2,3-dihydroxybenzoic acid (2,3-DHB), α,β,γ-resorcylicacid, protocatechuic acid, gentisic acid, piperonylic acid,3-methoxysalicylic acid, 4-methoxysalicylic acid, 5-methoxysalicylicacid, 6-methoxysalicylic acid, 3-hydroxy-2-methoxybenzoic acid,4-hydroxy-2-methoxybenzoic acid, 5-hydroxy-2-methoxybenzoic acid,vanillic acid, isovanillic acid, 5-hydroxy-3-methoxybenzoic acid,2,3-dimethoxybenzoic acid, 2,4-dimethoxybenzoic acid,2,5-dimethoxybenzoic acid, 2,6-dimethoxybenzoic acid, veratric acid(3,4-dimethoxybenzoic acid), 3,5-dimethoxybenzoic acid, gallic acid,2,3,4-trihydroxybenzoic acid, 2,3,6-trihydroxybenzoic acid,2,4,5-trihydroxybenzoic acid, 3-O-methylgallic acid (3-OMGA),4-O-methylgallic acid (4-OMGA), 3,4-O-dimethylgallic acid, syringicacid, and 3,4,5-trimethoxybenzoic acid.

22. The compound or composition of paragraph 20 wherein the heteroarylcarboxylic acid is selected from the group consisting of nicotinic acid,isonicotinic acid, picolinic acid, 3-hydroxypicolinic acid,6-hydroxynicotinic acid, citrazinic acid, 2,6-dihydroxynicotinic acid,kynurenic acid, xanthurenic acid, 6-hydroxykynurenic acid,8-methoxykynurenic acid, 7,8-dihydroxykynurenic acid, and7,8-dihydro-7,8-dihydroxykynurenic acid.

23. The compound or composition of paragraph 19, wherein the aromaticcarboxylic acid is a phenylacetate selected from the group consisting ofphenylacetic acid (hydratropic acid), 2-hydroxyphenylacetic acid,3-hydroxyphenylacetic acid, 4-hydroxyphenylacetic acid,homoprotocatechuic acid, homogentisic acid, 2,6-dihydroxyphenylaceticacid, homovanillic acid, homoisovanillic acid, homoveratric acid,atropic acid, d,l-tropic acid, diclofenac, d,l-mandelic acid,3,4-dihydroxy-d,l-mandelic acid, vanillyl-d,l-mandelic acid,isovanillyl-d,l-mandelic acid, ibuprofen, fenoprofen, carprofen,flurbiprofen, ketoprofen, and naproxen.

24. The compound or composition of paragraph 19, wherein the aromaticcarboxylic acid is a benzylacetate selected from the group consisting ofbenzylacetic acid, melilotic acid, 3-hydroxyphenylpropanoic acid,4-hydroxyphenylpropanoic acid, 2,3-dihydroxyphenylpropanoic acid,d,l-phenyllactic acid, o,m,p-hydroxy-d,l-phenyllactic acid, andphenylpyruvic acid.

25. The compound or composition of paragraph 19, wherein the aromaticcarboxylic acid is a cinnamate, selected from the group consisting ofcinnamic acid, o,m,p-coumaric acid, 2,3-dihydroxycinnamic acid,2,6-dihydroxycinnamic acid, caffeic acid, ferulic acid, isoferulic acid,5-hydroxyferulic acid, sinapic acid, and 2-hydroxy-3-phenylpropenoicacid.

26. The compound or composition of paragraph 4 or 6, wherein thecarboxylic acid is a dicarboxylic acid of the general formulaHOOC—R—COOH, where R is selected from the group consisting of an alkyl,alkenyl, alkynyl, aryl group, and derivatives thereof.

27. The compound or composition of paragraph 26, wherein thedicarboxylic acid is selected from the group consisting of oxalic,malonic, succinic, glutaric, adipic, pimelic, suberic, azelaic, sebacic,brassylic, thapsic, malic, tartaric, dihydroxymesoxalic,α-hydroxyglutaric, methylmalonic, meglutol, diaminopimelic, carbamoylaspartic, fumaric, maleic, mesaconic, 3-methylglutaconic, traumatic,phthalic acid, isophthalic, terephthalic, and dipicolinic acid.

28. The compound or composition of paragraph 4 or 6, wherein thecarboxylic acid is a polycarboxylic acid selected from the groupconsisting of citric acid, isocitric, carballylic, and trimesic acid.

29. The compound or composition of paragraph 1, wherein G¹ is at leastone polyethylene glycol.

30. The compound or composition of paragraph 29, wherein the terminalhydroxyl group of the polyethylene glycol is substituted with an amino,azide, or methoxy group.

31. The compound or composition of paragraph 1, wherein L¹ and Y¹ areabsent, G¹ is at least one vitamin compound, and m is 1-3.

32. The compound or composition of paragraph 1 or 31 wherein the atleast one vitamin compound is selected from ascorbic acid, riboflavin,thiamin, pantothenic acid, pyridoxine, pyridoxamine, pyridoxal, biotin,folic acid, niacin, pantothenic acid, retinol, cholecalciferol,ergocalciferol, and tocopherols.

33. The compound or composition of paragraph 1, wherein the at least oneconjugate of dextrorphan comprises 3-(N-acetyl-Val)-dextrorphan havingthe following structural formula, or a pharmaceutically acceptable saltthereof:

34. The compound or composition of paragraph 1 wherein the at least oneconjugate of dextrorphan comprises3-(N-acetyl-Val-OCH₂OC(O))-dextrorphan having the following structuralformula, or a pharmaceutically acceptable salt thereof:

35. The compound or composition of paragraph 1 wherein the at least oneconjugate of dextrorphan comprises 3-Val-dextrorphan having thefollowing structure, or a pharmaceutically acceptable salt thereof:

36. A compound or composition comprising at least one conjugate ofdextrorphan having the following general formula:

-   -   where L² is absent, or is

-   -   Y² is absent, or [A-X—Z]_(n)    -   where A, X, Z are independently absent or selected from —O—, —S—        or —(CR¹R²)_(k)—    -   J is [M-W]_(p)    -   where M is absent, or —(CR³R⁴)_(q)—; and W is absent, or —O— or        —S—    -   R¹, R², R³, R⁴ are each independently selected from H, alkyl,        aryl, alkylaryl, alkoxy, haloalkyl, or haloaryl    -   n and k are independently 1-4    -   p and q are independently 1-4    -   G_(m) ² is absent or selected independently for each repeating        subunit from H, oxoacid, polyethylene glycol having from 2 to 5        ethylene oxide units, or a vitamin compound, and m is 1-4,        except m is 1 when G² is H;    -   or a pharmaceutically acceptable salt thereof.

37. The compound or composition of paragraph 36, wherein G² is at leastone oxoacid, and m is 1-3.

38. The compound or composition of paragraph 37, wherein the at leastone oxoacid is at least one carboxylic acid is selected from the groupconsisting of aliphatic carboxylic acid, aryl carboxylic acid,dicarboxylic acid, polycarboxylic acid, and combinations thereof.

39. The compound or composition of paragraph 37, wherein the oxoacid isat least one amino acid selected from standard amino acids, non-standardamine acids, synthetic amino acids, and combinations thereof.

40. The compound or composition of paragraph 37, wherein the at leastone oxoacid is a combination of at least one carboxylic acid selectedfrom the group consisting of aliphatic carboxylic acid, aryl carboxylicacid, dicarboxylic acid, polycarboxylic acid, and combinations thereof,and at least one amino acid selected from the group consisting ofstandard amino acids, non-standard amine acids, synthetic amino acids,and combinations thereof.

41. The compound or composition of paragraph 38 or 40, wherein thecarboxylic acid is an aliphatic carboxylic acid selected from the groupconsisting of saturated carboxylic acids, monounsaturated carboxylicacids, polyunsaturated carboxylic acids, acetylenic carboxylic acids,substituted carboxylic acids, heteroatom containing carboxylic acids andring containing carboxylic acids.

42. The compound or composition of paragraph 41, wherein the saturatedcarboxylic acid is selected from the group consisting of methanoic,ethanoic, propanoic, butanoic, pentanoic, hexanoic, heptanoic, octanoic,2-propylpentanoic acid, pivalic acid, nonanoic, decanoic, dodecanoic,tetradecanoic, hexadecanoic, heptadecanoic, octadecanoic, and eicosanoicacid.

43. The compound or composition of paragraph 41, wherein themonounsaturated carboxylic acid is selected from the group consisting of4-decenoic, 9-decenoic, 5-lauroleic, 4-dodecenoic, 9-tetradecenoic,5-tetradecenoic, 4-tetradecenoic, 9-hexadecenoic, 6-hexadecenoic,6-octadecenoic, and 9-octadecenoic acid.

44. The compound or composition of paragraph 41, wherein thepolyunsaturated carboxylic acid is selected from the group consisting ofsorbic, octadecadienoic, octadecatrienoic, octadecatetraenoic,eicosatrienoic, eicosatetraenoic, eicosapentaenoic, docosapentaenoic,and docosahexaenoic acids.

45. The compound or composition of paragraph 41, wherein the acetyleniccarboxylic acid is selected from the group consisting of octadecynoic,octadecenynoic, 6,9-octadecenynoic, heptadecenynoic,tridecatetraenediynoic, tridecadienetriynoic, octadecadienediynoic,heptadecadienediynoic, octadecadienediynoic, octadecenediynoic, andoctadecenetriynoic acids.

46. The compound or composition of paragraph 41, wherein the substitutedcarboxylic acid is selected from the group consisting ofmethylpropanoic, isovaleric, methylhexadecanoic, 8-methyl-6-nonenoic,methyloctadecanoic, trimethyloctacosanoic, trimethyltetracosenoic,heptamethyltriacontanoic, tetramethylhexadecanoic,tetramethylpentadecanoic, lactic, glyceric, glycolic, threonic,3-hydroxypropionic, hydroxyoctadecatrienoic, hydroxyoctadecenoic,hydroxytetracosanoic, 2-hydroxybutyric, 3-hydroxybutyric,4-hydroxybutyric, 4-hydroxypentanoic, hydroxyoctadecadienediynoic,hydroxyoctadecadienoic, 10-hydroxydecanoic, hydroxydecenoic,hydroxyeicosenoic, hydroxyeicosadienoic, hydroxyhexadecanoic,dihydroxytetracosenoic, dihydroxydocosanoic, hydroxydocosanoic,trihydroxyoctadecanoic, trihydroxyhexadecanoic,trihydroxyicosahexaenoic, trihydroxyicosapentaenoic,2-methoxy-5-hexadecenoic, 2-methoxy hexadecanoic,7-methoxy-4-tetradecenoic, 9-methoxypentadecanoic,11-methoxyheptadecanoic, 3-methoxydocosanoic, diacetoxydocosanoic,2-acetoxydocosanoic, 2-acetoxytetracosanoic, 2-acetoxyhexacosanoic,9-oxononanoic, oxodecanoic, oxododecenoic, hydroxyoxodecenoic,10-oxo-8-decenoic, fluorooctadecenoic, fluorodecanoic,fluorotetradecanoic, fluorohexadecanoic, fluorooctadecadienoic,chlorohydroxyhexadecanoic, chlorohydroxyoctadecanoic,dichlorooctadecanoic, 3-bromo-2-nonaenoic, 9,10-dibromooctadecanoic,9,10,12,13-tetrabromooctadecanoic, 10-nitro-9,12-octadecadienoic,12-nitro-9,12-octadecadienoic, 9-nitro-9-octadecenoic, 9-oxo-2-decenoic,9-oxo-13-octadecenoic, oxooctadecatrienoic, 15-oxo-18-tetracosenoic,17-oxo-20-hexacosenoic, and 19-oxo-22-octacosenoic acids.

47. The compound or composition of paragraph 41, wherein the heteroatomcontaining carboxylic acid is selected from the group consisting of9-(1,3-nonadienoxy)-8-nonenoic, 9-(1,3,6-nonatrienoxy)-8-nonenoic,12-(1-hexenoxy)-9,11-dodecadienoic,12-(1,3-hexadienoxy)-9,11-dodecadienoic, 2-dodecylsulfanylacetic,2-tetradecylsulfanylacetic, 3-tetradecylsulfanylprop-2-enoic, and3-tetradecylsulfanylpropanoic acid.

48. The compound or composition of paragraph 41, wherein the ringcontaining carboxylic acid is selected from the group consisting of10-(2-Hexylcyclopropyl)decanoic,3-(2-[6-bromo-3,5-nondienylcyclopropyl)propanoic,9-(2-hexadecylcyclopropylidene)non-5-enoic,8-(2-octyl-1-cyclopropenyl)octanoic,7-(2-octyl-1-cyclopropenyl)heptanoic, 9,10-epoxyoctadecanoic,9,10-epoxy12-octadecenoic, 12,13-epoxy-9-octadecenoic,14,15-epoxy-11-eicosenoic, 11-(2-cyclopenten-1-yl)undecanoic,13-(2-cyclopenten-1-yl)tridecanoic, 13-(2-cyclopentenyl)-6-tridecenoic,11-cyclohexylundecanoic, 13-cyclohexyltridecanoic,7-(3,4-dimethyl-5-pentylfuran-2-yl)heptanoic,9-(4-methyl-5-pentylfuran-2-yl)nonanoic, 4-[5]-ladderane-butanoic,6-[5]-ladderane-hexanoic, and 6-[3]-ladderane-hexanoic acid.

49. The compound or composition of paragraph 38 or 40, wherein thecarboxylic acid is an aromatic carboxylic acid.

50. The compound or composition of paragraph 49, wherein the aromaticcarboxylic acid is selected from the group consisting of benzoic acid,hydroxybenzoate, heteroaryl carboxylic acid, and combinations thereof.

51 The compound or composition of paragraph 50, wherein thehydroxybenzoate is selected from the group consisting of salicylic acid,acetylsalicylic acid (aspirin), 3-hydroxybenzoic acid, 4-hydroxybenzoicacid, 6-methylsalicylic acid, o,m,p-cresotinic acid, anacardic acids,4,5-dimethylsalicylic acid, o,m,p-thymotic acid, diflunisal,o,m,p-anisic acid, 2,3-dihydroxybenzoic acid (2,3-DHB), α,β,γ-resorcylicacid, protocatechuic acid, gentisic acid, piperonylic acid,3-methoxysalicylic acid, 4-methoxysalicylic acid, 5-methoxysalicylicacid, 6-methoxysalicylic acid, 3-hydroxy-2-methoxybenzoic acid,4-hydroxy-2-methoxybenzoic acid, 5-hydroxy-2-methoxybenzoic acid,vanillic acid, isovanillic acid, 5-hydroxy-3-methoxybenzoic acid,2,3-dimethoxybenzoic acid, 2,4-dimethoxybenzoic acid,2,5-dimethoxybenzoic acid, 2,6-dimethoxybenzoic acid, veratric acid(3,4-dimethoxybenzoic acid), 3,5-dimethoxybenzoic acid, gallic acid,2,3,4-trihydroxybenzoic acid, 2,3,6-trihydroxybenzoic acid,2,4,5-trihydroxybenzoic acid, 3-O-methylgallic acid (3-OMGA),4-O-methylgallic acid (4-OMGA), 3,4-O-dimethylgallic acid, syringicacid, and 3,4,5-trimethoxybenzoic acid.

52. The compound or composition of paragraph 50, wherein the heteroarylcarboxylic acid is selected from the group consisting of nicotinic acid,isonicotinic acid, picolinic acid, 3-hydroxypicolinic acid,6-hydroxynicotinic acid, citrazinic acid, 2,6-dihydroxynicotinic acid,kynurenic acid, xanthurenic acid, 6-hydroxykynurenic acid,8-methoxykynurenic acid, 7,8-dihydroxykynurenic acid, and7,8-dihydro-7,8-dihydroxykynurenic acid.

53. The compound or composition of paragraph 49, wherein the carboxylicacid is a phenylacetate, a branched phenylpropionate, an unbranchedphenylpropionate (benzylacetate), a phenylpropenoate (cinnamate), saltsthereof, derivatives thereof, or a combination thereof.

54. The compound or composition of paragraph 53, wherein thephenylacetate is selected from the group consisting of phenylacetic acid(hydratropic acid), 2-hydroxyphenylacetic acid, 3-hydroxyphenylaceticacid, 4-hydroxyphenylacetic acid, homoprotocatechuic acid, homogentisicacid, 2,6-dihydroxyphenylacetic acid, homovanillic acid, homoisovanillicacid, homoveratric acid, atropic acid, d,l-tropic acid, diclofenac,d,l-mandelic acid, 3,4-dihydroxy-d,l-mandelic acid,vanillyl-d,l-mandelic acid, isovanillyl-d,l-mandelic acid, ibuprofen,fenoprofen, carprofen, flurbiprofen, ketoprofen, and naproxen.

55. The compound or composition of paragraph 49, wherein the carboxylicacid is a benzylacetate selected from the group consisting ofbenzylacetic acid, melilotic acid, 3-hydroxyphenylpropanoic acid,4-hydroxyphenylpropanoic acid, 2,3-dihydroxyphenylpropanoic acid,d,l-phenyllactic acid, o,m,p-hydroxy-d,l-phenyllactic acid, andphenylpyruvic acid.

56. The compound or composition of paragraph 49, wherein the carboxylicacid is a cinnamate, derivatives thereof, or combinations thereof.

57. The compound or composition of paragraph 56, wherein the cinnamateis selected from the group consisting of cinnamic acid, o,m,p-coumaricacid, 2,3-dihydroxycinnamic acid, 2,6-dihydroxycinnamic acid, caffeicacid, ferulic acid, isoferulic acid, 5-hydroxyferulic acid, sinapicacid, and 2-hydroxy-3-phenylpropenoic acid.

58. The compound or composition of paragraph 38 or 40, wherein thedicarboxylic acid is of the general formula HOOC—R—COOH, where R isselected from the group consisting of an alkyl, alkenyl, alkynyl,arylgroup, and derivatives thereof.

59. The compound or composition of paragraph 58, wherein thedicarboxylic acid is selected from the group consisting of oxalic,malonic, succinic, glutaric, adipic, pimelic, suberic, azelaic, sebacic,brassylic, thapsic, malic, tartaric, dihydroxymesoxalic,α-hydroxyglutaric, methylmalonic, meglutol, diaminopimelic, carbamoylaspartic, fumaric, maleic, mesaconic, 3-methylglutaconic, traumatic,phthalic acid, isophthalic, terephthalic, and dipicolinic acid.

60. The compound or composition of paragraph 38 or 40, wherein thepolycarboxylic acid is selected from the group consisting of citricacid, isocitric, carballylic, and trimesic acid.

61. The compound or composition of paragraph 39 or 40, wherein the aminoacid is a standard amino acid.

62. The compound or composition of paragraph 39 or 40, wherein the aminoacid is a non-standard amino acid or a synthetic amino acid.

63. The compound or composition of paragraph 36, wherein G² is at leastone polyethylene glycol, and m is 13.

64. The compound or composition of paragraph 63, wherein the terminalhydroxyl group of the polyethylene glycol is substituted with an amino,azide, or methoxy group.

65. The compound or composition of paragraph 36, wherein G² is at leastone vitamin compound, and m is 13.

66. The compound or composition of paragraph 65 wherein the at least onevitamin compound is selected from ascorbic acid, riboflavin, thiamin,pantothenic acid, pyridoxine, pyridoxamine, pyridoxal, biotin, folicacid, niacin, pantothenic acid, retinol, cholecalciferol,ergocalciferol, and tocopherols.

67. The compound or composition of paragraph 36 wherein the at least oneconjugate of dextrorphan comprises N-(acetyl-OCH₂)-dextrorphanium havingthe following structural formula, or a pharmaceutically acceptable saltthereof:

68. A compound or composition comprising at least one conjugate ofdextrorphan having the following general formula:

-   -   where L¹ and L² are independently absent, or

-   -   Y¹ and Y² are independently either absent, or [A-X—Z]_(n)    -   where A, X, Z are independently selected for Y¹ and Y², and are,        independent of each other, either absent or selected from —O—,        —S—, or —(CR¹R²)_(k)—    -   J is [M-W]_(p)    -   where M is absent, or —(CR³R⁴)_(q)—; and W is absent, or —O— or        —S—    -   R¹ and R² are each independently selected for Y¹ and Y², and        are, independent of each other, selected from H, alkyl, aryl,        alkylaryl, alkoxy, haloalkyl, or haloaryl    -   R³ and R⁴ are each independently selected from H, alkyl, aryl,        alkylaryl, alkoxy, haloalkyl, or haloaryl    -   for each Y¹ and Y², n is independently an integer of 1-4    -   for each repeating unit of [A-X—Z]_(n), when —(CR¹R²)_(k)— is        present, k is independently an integer of 1-4.    -   p and q are independently 1-4    -   G_(m) ¹ and G_(m) ² are independently absent, or selected        independently of each other and, when present, each repeating        subunit is independently selected from H, oxoacid, polyethylene        glycol having from 2 to 5 ethylene oxide units, or a vitamin        compound;    -   where m is selected independently for G¹ and G², and is an        integer of 1-4, except that m is 1 when G¹ or G² is a hydrogen        atom;    -   or a pharmaceutically acceptable salt thereof.

69. The compound or composition of paragraph 68, wherein L¹ and Y¹ areabsent, G¹ is at least one oxoacid, and m is 1-3, and M is—(CR³R⁴)_(q)—; W is O or absent, L² and Y² are absent, G² is at leastone oxoacid, and m is 1-3.

70. The compound or composition of paragraph 68, wherein L¹ and Y¹ arepresent, A is O, X is —(CR¹R²)_(k)—, Z is O, G¹ is at least one oxoacid,and m is 1-3, and M is —(CR³R⁴)_(q)—; W is O or absent, L² and Y² areabsent, G² is at least one oxoacid, and m is 1-3.

71. The compound or composition of paragraph 69 or 70, wherein the atleast one oxoacid is at least one carboxylic acid selected from thegroup consisting of aliphatic carboxylic acid, aryl carboxylic acid,dicarboxylic acid, polycarboxylic acid, and combinations thereof.

72. The compound or composition of paragraph 69 or 70, wherein the atleast one oxoacid is at least one amino acid selected from standardamino acids, non-standard amino acids, synthetic amino acids, andcombinations thereof.

73. The compound or composition of paragraph 68, 69, or 70, wherein G¹and/or G² is a combination of at least one oxoacid selected from thegroup consisting of aliphatic carboxylic acid, aryl carboxylic acid,dicarboxylic acid, polycarboxylic acid, and combinations thereof, and atleast one amino acid selected from the group consisting of standardamino acids, non-standard amino acids, synthetic amino acids, andcombinations thereof.

74. The compound or composition of paragraph 72 or 73, wherein the atleast one amino acid is a standard amino acid.

75. The compound or composition of paragraph 72 or 73, wherein the atleast one amino acid is a non-standard amino acid.

76. The compound or composition of paragraph 72 or 73, wherein the atleast one amino acid is a synthetic amino acid.

77. The compound or composition of paragraph 72 or 73, wherein the atleast one amino acid is valine.

78. The compound or composition of paragraph 71 or 73, wherein thecarboxylic acid is an aliphatic carboxylic acid selected from the groupconsisting of saturated carboxylic acids, monounsaturated carboxylicacids, polyunsaturated carboxylic acids, acetylenic carboxylic acids,substituted carboxylic acids, heteroatom containing carboxylic acids andring containing carboxylic acids.

79. The compound or composition of paragraph 78, wherein the saturatedcarboxylic acid is selected from the group consisting of methanoic,ethanoic, propanoic, butanoic, pentanoic, hexanoic, heptanoic, octanoic,2-propylpentanoic acid, pivalic acid, nonanoic, decanoic, dodecanoic,tetradecanoic, hexadecanoic, heptadecanoic, octadecanoic, and eicosanoicacid.

80. The compound or composition of paragraph 78, wherein themonounsaturated carboxylic acid is selected from the group consisting of4-decenoic, 9-decenoic, 5-lauroleic, 4-dodecenoic, 9-tetradecenoic,5-tetradecenoic, 4-tetradecenoic, 9-hexadecenoic, 6-hexadecenoic,6-octadecenoic, and 9-octadecenoic acid.

81. The compound or composition of paragraph 78, wherein thepolyunsaturated carboxylic acid is selected from the group consisting ofsorbic, octadecadienoic, octadecatrienoic, octadecatetraenoic,eicosatrienoic, eicosatetraenoic, eicosapentaenoic, docosapentaenoic,and docosahexaenoic acids.

82. The compound or composition of paragraph 78, wherein the acetyleniccarboxylic acid is selected from the group consisting of octadecynoic,octadecenynoic, 6,9-octadecenynoic, heptadecenynoic,tridecatetraenediynoic, tridecadienetriynoic, octadecadienediynoic,heptadecadienediynoic, octadecadienediynoic, octadecenediynoic, andoctadecenetriynoic acids.

83. The compound or composition of paragraph 78, wherein the substitutedcarboxylic acid is selected from the group consisting ofmethylpropanoic, isovaleric, methylhexadecanoic, 8-methyl-6-nonenoic,methyloctadecanoic, trimethyloctacosanoic, trimethyltetracosenoic,heptamethyltriacontanoic, tetramethylhexadecanoic,tetramethylpentadecanoic, lactic, glyceric, glycolic, threonic,3-hydroxypropionic, hydroxyoctadecatrienoic, hydroxyoctadecenoic,hydroxytetracosanoic, 2-hydroxybutyric, 3-hydroxybutyric,4-hydroxybutyric, 4-hydroxypentanoic, hydroxyoctadecadienediynoic,hydroxyoctadecadienoic, 10-hydroxydecanoic, hydroxydecenoic,hydroxyeicosenoic, hydroxyeicosadienoic, hydroxyhexadecanoic,dihydroxytetracosenoic, dihydroxydocosanoic, hydroxydocosanoic,trihydroxyoctadecanoic, trihydroxyhexadecanoic,trihydroxyicosahexaenoic, trihydroxyicosapentaenoic,2-methoxy-5-hexadecenoic, 2-methoxy hexadecanoic,7-methoxy-4-tetradecenoic, 9-methoxypentadecanoic,11-methoxyheptadecanoic, 3-methoxydocosanoic, diacetoxydocosanoic,2-acetoxydocosanoic, 2-acetoxytetracosanoic, 2-acetoxyhexacosanoic,9-oxononanoic, oxodecanoic, oxododecenoic, hydroxyoxodecenoic,10-oxo-8-decenoic, fluorooctadecenoic, fluorodecanoic,fluorotetradecanoic, fluorohexadecanoic, fluorooctadecadienoic,chlorohydroxyhexadecanoic, chlorohydroxyoctadecanoic,dichlorooctadecanoic, 3-bromo-2-nonaenoic, 9,10-dibromooctadecanoic,9,10,12,13-tetrabromooctadecanoic, 10-nitro-9,12-octadecadienoic,12-nitro-9,12-octadecadienoic, 9-nitro-9-octadecenoic, 9-oxo-2-decenoic,9-oxo-13-octadecenoic, oxooctadecatrienoic, 15-oxo-18-tetracosenoic,17-oxo-20-hexacosenoic, and 19-oxo-22-octacosenoic acids.

84. The compound or composition of paragraph 78, wherein the heteroatomcontaining carboxylic acid is selected from the group consisting of9-(1,3-nonadienoxy)-8-nonenoic, 9-(1,3,6-nonatrienoxy)-8-nonenoic,12-(1-hexenoxy)-9,11-dodecadienoic,12-(1,3-hexadienoxy)-9,11-dodecadienoic, 2-dodecylsulfanylacetic,2-tetradecylsulfanylacetic, 3-tetradecylsulfanylprop-2-enoic, and3-tetradecylsulfanylpropanoic acid.

85. The compound or composition of paragraph 78, wherein the ringcontaining carboxylic acid is selected from the group consisting of10-(2-Hexylcyclopropyl)decanoic,3-(2-[6-bromo-3,5-nondienylcyclopropyl)propanoic,9-(2-hexadecylcyclopropylidene)non-5-enoic,8-(2-octyl-1-cyclopropenyl)octanoic,7-(2-octyl-1-cyclopropenyl)heptanoic, 9,10-epoxyoctadecanoic,9,10-epoxy12-octadecenoic, 12,13-epoxy-9-octadecenoic,14,15-epoxy-11-eicosenoic, 11-(2-cyclopenten-1-yl)undecanoic,13-(2-cyclopenten-1-yl)tridecanoic, 13-(2-cyclopentenyl)-6-tridecenoic,11-cyclohexylundecanoic, 13-cyclohexyltridecanoic,7-(3,4-dimethyl-5-pentylfuran-2-yl)heptanoic,9-(4-methyl-5-pentylfuran-2-yl)nonanoic, 4-[5]-ladderane-butanoic,6-[5]-ladderane-hexanoic, and 6-[3]-ladderane-hexanoic acid.

86. The compound or composition of paragraph 71 or 73, wherein thecarboxylic acid is an aromatic carboxylic acid.

87. The compound or composition of paragraph 86 wherein the carboxylicacid is selected from the group consisting of benzoic acid,hydroxybenzoate, heteroaryl carboxylic acid, and combinations thereof.

88. The compound or composition of paragraph 87 wherein thehydroxybenzoate is selected from the group consisting of salicylic acid,acetylsalicylic acid (aspirin), 3-hydroxybenzoic acid, 4-hydroxybenzoicacid, 6-methylsalicylic acid, o,m,p-cresotinic acid, anacardic acids,4,5-dimethylsalicylic acid, o,m,p-thymotic acid, diflunisal,o,m,p-anisic acid, 2,3-dihydroxybenzoic acid (2,3-DHB), α,β,γ-resorcylicacid, protocatechuic acid, gentisic acid, piperonylic acid,3-methoxysalicylic acid, 4-methoxysalicylic acid, 5-methoxysalicylicacid, 6-methoxysalicylic acid, 3-hydroxy-2-methoxybenzoic acid,4-hydroxy-2-methoxybenzoic acid, 5-hydroxy-2-methoxybenzoic acid,vanillic acid, isovanillic acid, 5-hydroxy-3-methoxybenzoic acid,2,3-dimethoxybenzoic acid, 2,4-dimethoxybenzoic acid,2,5-dimethoxybenzoic acid, 2,6-dimethoxybenzoic acid, veratric acid(3,4-dimethoxybenzoic acid), 3,5-dimethoxybenzoic acid, gallic acid,2,3,4-trihydroxybenzoic acid, 2,3,6-trihydroxybenzoic acid,2,4,5-trihydroxybenzoic acid, 3-O-methylgallic acid (3-OMGA),4-O-methylgallic acid (4-OMGA), 3,4-O-dimethylgallic acid, syringicacid, and 3,4,5-trimethoxybenzoic acid.

89. The compound or composition of paragraph 87 wherein the heteroarylcarboxylic acid is selected from the group consisting of nicotinic acid,isonicotinic acid, picolinic acid, 3-hydroxypicolinic acid,6-hydroxynicotinic acid, citrazinic acid, 2,6-dihydroxynicotinic acid,kynurenic acid, xanthurenic acid, 6-hydroxykynurenic acid,8-methoxykynurenic acid, 7,8-dihydroxykynurenic acid, and7,8-dihydro-7,8-dihydroxykynurenic acid.

90. The compound or composition of paragraph 86, wherein the aromaticcarboxylic acid is a phenylacetate selected from the group consisting ofphenylacetic acid (hydratropic acid), 2-hydroxyphenylacetic acid,3-hydroxyphenylacetic acid, 4-hydroxyphenylacetic acid,homoprotocatechuic acid, homogentisic acid, 2,6-dihydroxyphenylaceticacid, homovanillic acid, homoisovanillic acid, homoveratric acid,atropic acid, d,l-tropic acid, diclofenac, d,l-mandelic acid,3,4-dihydroxy-d,l-mandelic acid, vanillyl-d,l-mandelic acid,isovanillyl-d,l-mandelic acid, ibuprofen, fenoprofen, carprofen,flurbiprofen, ketoprofen, and naproxen.

91. The compound or composition of paragraph 86, wherein the aromaticcarboxylic acid is a benzylacetate selected from the group consisting ofbenzylacetic acid, melilotic acid, 3-hydroxyphenylpropanoic acid,4-hydroxyphenylpropanoic acid, 2,3-dihydroxyphenylpropanoic acid,d,l-phenyllactic acid, o,m,p-hydroxy-d,l-phenyllactic acid, andphenylpyruvic acid.

92. The compound or composition of paragraph 86, wherein the aromaticcarboxylic acid is a cinnamate, selected from the group consisting ofcinnamic acid, o,m,p-coumaric acid, 2,3-dihydroxycinnamic acid,2,6-dihydroxycinnamic acid, caffeic acid, ferulic acid, isoferulic acid,5-hydroxyferulic acid, sinapic acid, and 2-hydroxy-3-phenylpropenoicacid.

93. The compound or composition of paragraph 71 or 73, wherein thecarboxylic acid is a dicarboxylic acid of the general formulaHOOC—R—COOH, where R is selected from the group consisting of an alkyl,alkenyl, alkynyl, arylgroup, and derivatives thereof.

94. The compound or composition of paragraph 93, wherein thedicarboxylic acid is selected from the group consisting of oxalic,malonic, succinic, glutaric, adipic, pimelic, suberic, azelaic, sebacic,brassylic, thapsic, malic, tartaric, dihydroxymesoxalic,α-hydroxyglutaric, methylmalonic, meglutol, diaminopimelic, carbamoylaspartic, fumaric, maleic, mesaconic, 3-methylglutaconic, traumatic,phthalic acid, isophthalic, terephthalic, and dipicolinic acid.

95. The compound or composition of paragraph 71 or 73, wherein thecarboxylic acid is a polycarboxylic acid selected from the groupconsisting of citric acid, isocitric, carballylic, and trimesic acid.

96. The compound or composition of paragraph 68, wherein G¹ and/or G² isat least one polyethylene glycol.

97. The compound or composition of paragraph 96, wherein the terminalhydroxyl group of the polyethylene glycol is substituted with an amino,azide, or methoxy group.

98. The compound or composition of paragraph 68, wherein G¹ and/or G² isat least one vitamin compound, and m is 1-3.

99. The compound or composition of paragraph 98 wherein the at least onevitamin compound is selected from ascorbic acid, riboflavin, thiamin,pantothenic acid, pyridoxine, pyridoxamine, pyridoxal, biotin, folicacid, niacin, pantothenic acid, retinol, cholecalciferol,ergocalciferol, and tocopherols.

100. The compound or composition of paragraph 68 wherein the at leastone conjugate of dextrorphan comprises3-acetyl-N-(acetyl-OCH₂)-dextrorphanium having the following structuralformula, or a pharmaceutically acceptable salt thereof:

101. The compound or composition of any one of paragraphs 1-100, whereinthe pharmaceutically acceptable salt of the conjugate is apharmaceutically acceptable anionic salt form or salt mixtures thereof.

102. The compound or composition of paragraph 101, wherein the anionicsalt form is selected from the group consisting of acetate, l-aspartate,besylate, bicarbonate, carbonate, d-camsylate, l-camsylate, citrate,edisylate, formate, fumarate, gluconate, hydrobromide/bromide,hydrochloride/chloride, d-lactate, i-lactate, d,l-lactate, d,l-malate,l-malate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate,d-tartrate, l-tartrate, d,l-tartrate, meso-tartrate, benzoate,gluceptate, d-glucuronate, hybenzate, isethionate, malonate,methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate,tosylate, thiocyanate, acefyllinate, aceturate, aminosalicylate,ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate,hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate,furate, fusidate, galactarate (mucate), galacturonate, gallate,gentisate, glutamate, glutarate, glycerophosphate, heptanoate(enanthate), hydroxybenzoate, hippurate, phenylpropionate, iodide,xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate,myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate,propionate, pyrophosphate, salicylate, salicylsulfate, sulfosalicylate,tannate, terephthalate, thiosalicylate, tribrophenate, valerate,valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate,esylate, glycolate, thiocyanate, or undecylenate.

103. The compound or composition of any one of paragraphs 1-102, whereinthe at least one conjugate is present in an amount of about 0.5 mg orhigher, about 2.5 mg or higher, about 5 mg or higher, about 10 mg orhigher, about 20 mg or higher, about 50 mg or higher, or about 100 mg orhigher.

104. The compound or composition of any one of paragraphs 1-103, whereinthe at least one conjugate is provided in a dosage form selected fromthe group consisting of: a tablet, a capsule, a caplet, a suppository, atroche, a lozenge, an oral powder, a solution, an oral film, a thinstrip, a slurry, and a suspension.

105. The compound or composition of any one of paragraphs 1-104, whereinthe at least one conjugate exhibits a slower rate of release over timeas compared to unmodified dextrorphan.

106. The composition of any one of paragraphs 1-105, wherein thecomposition further comprises one or more excipients.

107. The composition of paragraph 106, wherein the one or moreexcipients is at least one filler, at least one glidant, at least onebinder, at least one diluent, at least one lubricant, at least onesurfactant, at least one plasticizer, at least one disintegrant, or acombination thereof.

108. The composition of any one of paragraphs 1-107, wherein thecomposition further comprises at least one additional activepharmaceutical ingredient.

109. The composition of paragraph 108, wherein the additional activepharmaceutical ingredient is one or more of acetaminophen,phenylpropanolamine, ibuprofen, aspirin, diflusinal, salicylic acid,dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen,flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac,etodolac, ketorolac, diclofenac, piroxicam, meloxicam, tenoxicam,lornoxicam, isoxicam, mefenamic acid, meclofenamic acid, flufenamicacid, tolfenamic acid, celecoxib, valdecoxib, lumiracoxib, pheniramine,chlorpheniramine, fexofenadine, azelastine, hydroxyzine,diphenhydramine, desloratidine, loratidine, cyproheptadine,bromopheniramine, emedastine, levocabastine, carbinoxamine,levocetirizine, clemastine, cetirizine, phenylephrine, pseudoephedrine,oxymetazoline, pyrilamine, doxylamine, codeine, pholcodine,dextromethorphan, noscapine, butamirate, acetylcysteine, menthol,guaifenesin, or combinations thereof.

110. The composition of paragraph 108, wherein the additional activepharmaceutical ingredient is in the form of a second conjugate.

111. The composition of paragraph 110, wherein the second conjugate is adextrorphan conjugate that is different from the at least one conjugate.

112. A method of treating a patient having opioid dependence,hyperalgesia, pseudobulbar affect (PBA), neuropathy, diabetic peripheralneuropathic pain, catalepsy, amnesia, Alzheimer's disease, depression,post-traumatic stress disorder (PTSD), cough, impulse to cough,sneezing, itching of the nose, throat or watery eyes, nasal congestion,sinus congestion and pressure, sore throat, headache, muscular pain,fever, upper respiratory symptoms, or bronchial irritation, comprisingorally administering to the patient a pharmaceutically effective amountof a composition comprising at least one conjugate of dextrorphan and atleast one oxoacid, polyethylene glycol, vitamin compound, or acombination thereof.

113. The method of paragraph 112, wherein the patient is a pediatricpatient.

114. The method of paragraph 112, wherein the patient is an elderlypatient.

115. The method of paragraph 112, wherein the patient is a normativepatient.

116. The method of paragraph 112, wherein the patient is a neonatalpatient.

117. The method of paragraph 112, wherein the patient is an adolescentpatient.

118. A pharmaceutical kit comprising:

-   -   a specified amount of individual doses in a package, each dose        comprising    -   a pharmaceutically effective amount of at least one conjugate of        dextrorphan and at least one oxoacid, polyethylene glycol,        vitamin compound, or a combination thereof.

119. The pharmaceutical kit of paragraph 118, wherein the kit furthercomprises: instructions for use of the kit in a method for treatingcough, sneezing, itching of the nose, throat or watery eyes, nasalcongestion, sinus congestion and pressure, sore throat, headache,muscular pain, fever, upper respiratory symptoms, or bronchialirritation in a human or animal patient.

120. The pharmaceutical kit of paragraph 118 or 119, wherein the kitfurther comprises one or more additional compositions containing one ormore other active ingredients.

121. The pharmaceutical kit of paragraph 118 or 119, wherein theindividual doses in the kit comprise at least two different dosagestrengths of the at least one dextrorphan conjugate.

The presently described technology is now described in such full, clear,concise and exact terms as to enable any person skilled in the art towhich it pertains, to practice the same. It is to be understood that theforegoing describes preferred embodiments of the technology and thatmodifications may be made therein without departing from the spirit orscope of the invention as set forth in the appended claims.

What is claimed is:
 1. A compound having the following general formula:

where L¹ is absent, or is

Y¹ is absent, or [A-X—Z]_(n) where A, X, Z are independently absent orselected from —O—, —S— or —(CR¹R²)_(k)— R¹, R² are each independentlyselected from H, alkyl, aryl, alkyl aryl, alkoxy, haloalkyl, or haloaryln and k are independently selected from 1-4 G_(m) ¹ is selectedindependently for each repeating subunit from H, oxoacid, polyethyleneglycol having from 2 to 5 ethylene oxide units, or a vitamin compound,and m is 1-4, wherein when G¹ is H, m is 1 and k is 3 or 4, or when G¹is acetic acid, G¹ is attached via an ester bond; or a pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1, wherein L¹ and Y¹are present, G¹ is at least one oxoacid, and m is 1-3.
 3. The compoundof claim 1, wherein G¹ is at least one oxoacid selected from the groupconsisting of aliphatic carboxylic acid, aryl carboxylic acid,dicarboxylic acid, polycarboxylic acid, standard amino acids,non-standard amino acids, and synthetic amino acids, and combinationsthereof.
 4. The compound of claim 3 wherein G¹ is a combination of atleast two oxoacids, wherein at least one of the at least two oxoacids isselected from the group consisting of aliphatic carboxylic acid, arylcarboxylic acid, dicarboxylic acid, and polycarboxylic acid, andcombinations thereof, and at least one of the at least two oxoacids isselected from standard amino acids, non-standard amino acids, syntheticamino acids, and combinations thereof.
 5. The compound of claim 4,wherein the at least one of the at least two oxoacids is valine.
 6. Thecompound of claim 1, wherein the compound has a structural formulaselected from the group consisting of

and a pharmaceutically acceptable salt thereof.
 7. A compound having thefollowing general formula:

where L² is absent, or is

Y² is absent, or [A-X—Z]_(n) where A, X, Z are independently absent orselected from —O—, —S— or —(CR¹R²)_(k)— J is [M-W]_(p) where M is—(CR³R⁴)_(q)—; and W is absent, or —O— or —S— R¹, R², R³, R⁴ are eachindependently selected from H, alkyl, aryl, alkylaryl, alkoxy,haloalkyl, or haloaryl n and k are independently selected from 1-4 p andq are independently selected from 1-4 G_(m) ² is absent or selectedindependently for each repeating subunit from H, oxoacid, polyethyleneglycol having from 2 to 5 ethylene oxide units, or a vitamin compound,and m is 1-4, except m is 1 when G² is H; or a pharmaceuticallyacceptable salt thereof.
 8. The compound of claim 7, wherein where L²and Y² are absent, M is —(CR³R⁴)_(q), G² is at least one oxoacid, and mis 1-3.
 9. The compound of claim 7, wherein the at least one oxoacid isacetic acid.
 10. The compound of claim 7 wherein the compound isN-(acetyl-OCH₂)-dextrorphanium having the following structural formula:

or a pharmaceutically acceptable salt thereof.
 11. A compound having thefollowing general formula:

where L¹ and L² are independently absent, or

Y¹ and Y² are independently either absent, or [A-X—Z]_(n) where A, X, Zare independently selected for Y¹ and Y², and are, independent of eachother, either absent or selected from —O—, —S—, or —(CR¹R²)_(k)— J is[M-W]_(p) where M is —(CR³R⁴)_(q)—; and W is absent, or —O— or —S— R¹and R² are each independently selected for Y¹ and Y², and are,independent of each other, selected from H, alkyl, aryl, alkylaryl,alkoxy, haloalkyl, or haloaryl R³ and R⁴ are each independently selectedfrom H, alkyl, aryl, alkylaryl, alkoxy, haloalkyl, or haloaryl for eachY¹ and Y², n is independently an integer of 1-4 for each repeating unitof [A-X—Z]_(n), when —(CR¹R²)_(k)— is present, k is independently aninteger of 1-4. p and q are independently selected from 1-4 G_(m) ¹ andG_(m) ² are independently absent, or selected independently of eachother and, when present, each repeating subunit is independentlyselected from H, oxoacid, polyethylene glycol having from 2 to 5ethylene oxide units, or a vitamin compound; where m is selectedindependently for G¹ and G², and is an integer of 1-4, except that m is1 when G¹ or G² is a hydrogen atom; or a pharmaceutically acceptablesalt thereof.
 12. The compound of claim 11, wherein at least one of G¹and G² is at least one oxoacid.
 13. The compound of claim 12, wherein G¹and G² are each acetic acid.
 14. The compound of claim 11, wherein thecompound is 3-acetyl-N-(acetyl-OCH₂)-dextrorphanium having the followingstructural formula:

or a pharmaceutically acceptable salt thereof.
 15. A composition whereinthe composition comprises the compound of 39 or a pharmaceuticallyacceptable salt of the compound.
 16. A composition wherein thecomposition comprises the compound of claim 11 or a pharmaceuticallyacceptable salt of the compound.
 17. The composition of claim 15,wherein the pharmaceutically acceptable salt is selected from the groupconsisting of acetate, l-aspartate, besylate, bicarbonate, carbonate,d-camsylate, l-camsylate, citrate, edisylate, formate, fumarate,gluconate, hydrobromide/bromide, hydrochloride/chloride, d-lactate,i-lactate, d,l-lactate, d,l-malate, l-malate, mesylate, pamoate,phosphate, succinate, sulfate, bisulfate, d-tartrate, l-tartrate,d,l-tartrate, meso-tartrate, benzoate, gluceptate, d-glucuronate,hybenzate, isethionate, malonate, methylsulfate, 2-napsylate,nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate,acefyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate,camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate,dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate(mucate), galacturonate, gallate, gentisate, glutamate, glutarate,glycerophosphate, heptanoate (enanthate), hydroxybenzoate, hippurate,phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate,mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate,palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate,salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate,tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate,camsylate, octanoate, estolate, esylate, glycolate, thiocyanate,undecylenate, or combinations thereof.
 18. The composition of claim 16,wherein the pharmaceutically acceptable salt is selected from the groupconsisting of acetate, l-aspartate, besylate, bicarbonate, carbonate,d-camsylate, l-camsylate, citrate, edisylate, formate, fumarate,gluconate, hydrobromide/bromide, hydrochloride/chloride, d-lactate,i-lactate, d,l-lactate, d,l-malate, l-malate, mesylate, pamoate,phosphate, succinate, sulfate, bisulfate, d-tartrate, l-tartrate,d,l-tartrate, meso-tartrate, benzoate, gluceptate, d-glucuronate,hybenzate, isethionate, malonate, methylsulfate, 2-napsylate,nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate,acefyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate,camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate,dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate(mucate), galacturonate, gallate, gentisate, glutamate, glutarate,glycerophosphate, heptanoate (enanthate), hydroxybenzoate, hippurate,phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate,mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate,palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate,salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate,tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate,camsylate, octanoate, estolate, esylate, glycolate, thiocyanate,undecylenate, or combinations thereof.
 19. The composition of claim 15,wherein the compound is present in an amount of about 0.5 mg or higher.20. The composition of claim 16, wherein the compound is present in anamount of about 0.5 mg or higher.
 21. The composition of claim 15,wherein the compound is provided in a dosage form selected from thegroup consisting of a tablet, a capsule, a caplet, a suppository, atroche, a lozenge, an oral powder, a solution, a syrup, an oral film, athin strip, a slurry, and a suspension.
 22. The composition of claim 16,wherein the compound is provided in a dosage form selected from thegroup consisting of a tablet, a capsule, a caplet, a suppository, atroche, a lozenge, an oral powder, a solution, a syrup, an oral film, athin strip, a slurry, and a suspension.